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Progress in Neurobiology xxx (2013) xxxxxx

Contents lists available at ScienceDirect

Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio

The effects of psychotherapy on brain function: A systematic and

critical review
Alessio Barsaglini a,b, Giuseppe Sartori b, Stefania Benetti a, William Pettersson-Yeo a,
Andrea Mechelli a,*
a
Department of Psychosis Studies, Institute of Psychiatry, Kings College London, De Crespigny Park, London SE5 8AF, UK
b
Department of Psychology, University of Padua, Via Venezia, 8, 35100 Padova, Italy

A R T I C L E I N F O A B S T R A C T

Article history: Over the past two decades, the development of neuroimaging techniques has allowed the non-invasive
Received 27 September 2012 investigation of neuroplastic changes associated with psychotherapeutic treatment. The aim of the
Received in revised form 3 June 2013 present article is to present a systematic and critical review of longitudinal studies addressing the impact
Accepted 25 October 2013
of psychotherapy on the brain published to date. After summarizing the results reported in the literature for
Available online xxx
each psychiatric disorder separately (i.e. obsessive-compulsive disorder, panic disorder, unipolar major
depressive disorder, posttraumatic stress disorder, specic phobia, schizophrenia), we discuss the results
Keywords:
focusing on three questions of interest: (i) whether neurobiological changes which follow psychotherapy
Psychotherapy
Pharmacotherapy
occur in regions that showed signicant neurofunctional alteration pre-treatment; (ii) whether these
Brain neurobiological changes are similar, or different, to those observed following pharmacological treatment;
Neuroimaging and (iii) whether neurobiological changes could be used as an objective means of monitoring the progress
Plasticity and outcome of psychotherapy. The evidence reviewed indicates that (i) depending on the disorder under
investigation, psychotherapy results in either a normalisation of abnormal patterns of activity, the
recruitment of additional areas which did not show altered activation prior to treatment, or a combination
of the two; (ii) the effects of psychotherapy on brain function are comparable to those of medication for
some but not all disorders; and (iii) there is preliminary evidence that neurobiological changes are
associated with the progress and outcome of psychotherapy. It is hoped that a better understanding of the
impact of psychotherapy on brain function will eventually inform the development of new biologically
informed treatments and allow clinicians to make more effective treatment decisions.
2013 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.2. Selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2.3. Variables of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.1. Obsessive-compulsive disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.2. Panic disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

Abbreviations: ACC, anterior cingulate cortex; BADT, brief behavioural activation treatment for depression; BEP, brief eclectic psychotherapy; CBSST, cognitive behavioural
social skills training; CBT, cognitive behaviour therapy; CRT, cognitive remediation therapy; CT, computed tomography; DLPFC, dorsolateral prefrontal cortex; DSM,
Diagnostic and Statistical Manual of Mental Disorder; FG, fusiform gyrus; fMRI, functional magnetic resonance imaging; IFG, inferior frontal gyrus; IPL, inferior parietal
lobule; IPT, interpersonal therapy; LTC, lateral temporal cortex; MBRS, mindfulness-based stress reduction; MD, major depression; MFG, middle frontal gyrus; MPFC, medial
prefrontal cortex; MRI, magnetic resonance imaging; MRSI, magnetic resonance spectroscopy imaging; MTC, medial temporal cortex; OCD, obsessive-compulsive disorder;
OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PD, panic disorder; PE, prolonged exposure; PET, positron emission tomography; PFC, prefrontal cortex; PFMC,
prefrontal medial cortex; PHG, parahippocampal gyrus; PTSD, posttraumatic stress disorder; SFG, superior frontal gyrus; SPECT, single photon emission tomography; SRI,
serotonin reuptake inhibitor; STG, superior temporal gyrus; TAU, treatment as usual; vACC, ventral anterior cingulate cortex; VRET, virtual reality exposure therapy; Xe-CT,
xenon-enhanced computed tomography.
* Corresponding author. Tel.: +44 020 7848 0833.
E-mail address: a.mechelli@kcl.ac.uk (A. Mechelli).

0301-0082/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.pneurobio.2013.10.006

Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
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2 A. Barsaglini et al. / Progress in Neurobiology xxx (2013) xxxxxx

3.3. Depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

3.4. Posttraumatic stress disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.5. Specic phobia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3.6. Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

1. Introduction et al., 2011) and may inform the development and evaluation of
new biologically informed treatments.
Psychotherapy can have the most profound inuence on a
persons belief system, emotional state and behaviour, and it is 2. Methods
perhaps therefore not surprising that it may also lead to signicant
structural and functional changes in the brain (Kandel, 1998). A 2.1. Search strategy
better understanding of these neuroplastic changes has several
potential benets: rstly, it may provide an objective means of A systematic search strategy was used to identify suitable
monitoring the progress and outcome of psychotherapy in terms of publications. This involved an online search of the PubMed and
cortical reorganisation; secondly, it may provide insight into the Web of Science databases, using the search terms (psychothera-
neural basis of psychological recovery; and thirdly, it may inform py OR psychological intervention OR psychological therapy
the development of new biologically informed treatments. OR psychological treatment OR CBT OR cognitive-behavioural
In the 1880s, Sigmund Freuds attempt to translate psycho- therapy OR cognitive-behavioural therapy OR mindfulness
therapeutic concepts into the language of biology was greatly OR interpersonal therapy OR behavioural activation treatment
restricted by the limited neuroscientic knowledge available at the OR virtual reality exposure therapy or psychodynamic therapy
time (Freud, 1895). Over the past two decades however, the OR acceptance and commitment therapy OR remediation
development of a number of neuroimaging techniques has, for the therapy or cognitive remediation or social skills training)
rst time, allowed the non-invasive investigation of the neuro- AND (neuroimaging OR imaging OR MRI OR Magnetic
plastic change associated with psychotherapeutic treatment. Resonance Imaging OR PET OR Positron-Emission Tomogra-
These techniques include, amongst others, magnetic resonance phy OR SPECT OR Single-photon emission computed tomog-
imaging (MRI), positron emission tomography (PET) and single raphy OR NIRS OR Near-infrared spectroscopy OR
photon emission computed tomography (SPECT). Since then a spectroscopy) conducted on 4th March 2013 with no time span
growing number of neuroimaging studies have reported signi- specied for date of publication. A total of 1902 and 670 hits were
cant effects using a range of therapeutic approaches such as returned for the two databases respectively.
cognitive behavioural therapy (CBT), interpersonal therapy and
psychodynamic approaches, alongside different clinical popula- 2.2. Selection criteria
tions. Although several interesting reviews of these studies have
been published, most of them focused on either a specic Studies were included if they met the following criteria: (a)
treatment approach (Porto et al., 2009) or clinical population were reported in an original paper in a peer-reviewed journal, (b)
(Frewen et al., 2008; Sharpley, 2010), whilst those that did adopt a examined the impact of psychotherapy on brain function in
more comprehensive approach are now relatively dated (Kumari, psychiatric patients using functional neuroimaging methods
2006; Linden, 2006, 2008). which allowed the examination of specic regions; (c) employed
The aim of the present article therefore was to present a a longitudinal design in which the same patients were scanned
systematic and critical review of longitudinal studies published to before and after treatment (d) reported the results at group level
date, which examined the impact of psychotherapy on the brains of rather than in one or more single case studies. For the purpose of the
patients with psychiatric disorders. In order to facilitate interpre- present review, psychotherapy was dened as a clinical intervention
tation of the results, here we focus on studies that examined based on psychological principles; this means that it included both
groups of subjects, rather than single case studies, and which were computer-aided treatments (e.g. computerized cognitive beha-
carried out on adults rather than children. In the rst section of the vioural therapy) and treatments delivered by a mental health
article, we summarize the results reported in the literature for each professional (e.g. interpersonal psychotherapy). Studies focusing on
psychiatric disorder separately (i.e. obsessive-compulsive disor- the impact of psychotherapy in previous psychiatric patients who
der, panic disorder, unipolar major depressive disorder, posttrau- had already reached remission at the time of recruitment were not
matic stress disorder, specic phobia, schizophrenia). This section included. Studies using electrophysiological methods (e.g. electro-
includes both studies that investigated the neurobiological change encephalography) which did not allow the identication of specic
associated with psychotherapy alone and also studies that regions were also excluded. After applying these selection criteria,
compared this change with that associated with psychopharma- 42 papers were selected as relevant to the present review. In a
cological treatment. In the second section, we provide a critical second step, the reference lists of these 42 articles were manually
discussion of the results, focusing on three questions of interest checked for any additional studies not identied by the computer-
that have been the focus of the existing literature: (i) are ized literature search. This second step did not reveal any additional
neurobiological changes which follow psychotherapy located in studies, resulting in a nal sample of 42 articles to be included in our
the same or different regions to the ones which showed altered review. Although there was no language restriction, all the included
function before treatment? (ii) are these neurobiological changes articles were written in English.
similar or different to those which follow pharmacological
treatment? (iii) could neurobiological changes provide an objec- 2.3. Variables of interest
tive means of monitoring the progress and outcome of psycho-
therapy? The answers to these questions will be of interest to The following variables were examined for each article included
current biological models of symptomatic remission (e.g. Hofer in the review: number of patients receiving psychotherapy and

Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
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A. Barsaglini et al. / Progress in Neurobiology xxx (2013) xxxxxx
their demographics, type of psychotherapy, inclusion of a
comparison group of patients receiving pharmacotherapy and
their demographics, type of pharmacotherapy, inclusion of a
control group of patients on a waiting list and their demographics,
inclusion of a control group of healthy controls and their
demographics, neuroimaging technique used to examine brain
structure or function, any areas showing signicant alterations
before, or after, treatment relative to the control group, any areas
showing a signicant change in the patient group post-, relative to
pre-, treatment; any association between changes in brain function
and changes in symptom severity (if reported). A subset of this
information is reported in the tables.
3. Results
3.1. Obsessive-compulsive disorder
Obsessive-compulsive disorder (OCD) has been associated with
hypermetabolism in the orbitofrontal cortex, the anterior cingulate
gyrus and the head of the caudate nucleus (Del Casale et al., 2011;
Harrison et al., 2009; Radua and Mataix-Cols, 2009), and to date, a
large number of studies have examined the impact of psychother-
apy on brain function in patients with the disorder (see Table 1).
Baxter and colleagues (Baxter et al., 1992) for example measured
resting-state brain metabolism using FDG-PET in 18 patients
before and after the administration of either behavioural therapy,
or uoxetine, with 9 in each treatment group. Representing a core
strength of the study, a group of 4 healthy subjects was also
included to whom no treatment of any kind was applied. Based on
these cohorts, the authors found decreased rates of glucose
metabolism in the right head of the caudate nucleus in both
behavioural, and pharmacological, therapeutic responders com-
pared with pre-treatment. These decreases appeared to be specic
to good treatment response as they were not observed in either
non-responders or healthy subjects. Furthermore, there was a
signicant correlation between symptom improvement and
metabolic change in the right caudate in responders to pharmaco-
logical treatment, with a similar but non-signicant trend also
evident in those who had responded to behavioural therapy.
Within each hemisphere, there was also a signicant correlation of
activity between the orbital cortex and both the caudate nucleus
and the thalamus ipsilaterally in responders before, but not after,
treatment; again, this pattern of correlations was specic to
positive treatment response as it was not observed in either non-
responders or healthy subjects. These results suggest that the
impact of psychotherapy may be similar to that of pharmacother-
apy and affect not only regional activation but also the functional
integration amongst regions. However, it should be noted that the
treatment modality (i.e. behavioural therapy vs. uoxetine) was
chosen by the patients rather than randomly assigned. In a follow-
up study (Schwartz et al., 1996), the same research group
Table 1
Studies on the effects of psychotherapy on brain activity in OCD patients.
Study Psychotherapy (number of subjects)
Baxter et al. (1992) CBT (9)
Schwartz et al. (1996) CBT (9)
Saxena et al. (2009) Brief CBT (10)
Apostolova et al. (2010) CBT (9)
Nakatani et al. (2003) CBT (31)
Nakao et al. (2005) CBT (6)
Freyer et al. (2011) CBT (10)
Yamanishi et al. (2009) CBT (45)
ONeill et al. (2013) CBT (8)
CBT, cognitive behaviour therapy; CT, computed tomography; fMRI, functional magnetic resonance imaging; MRSI, magnetic resonance spectroscopy imaging; OCD,
obsessive-compulsive disorder; PET, positron emission tomography; SPECT, single photon emission tomography; Xe-CT, xenon-enhanced computed tomography.
Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
3
replicated the nding of decreased glucose metabolic rates in
the right caudate nucleus in 9 additional patients treated with
behavioural therapy. Moreover, the combination of the samples
from the two studies allowed detection of an additional effect, i.e. a
signicant decrease of activity in the left caudate nucleus after
treatment which, again, was evident in responders but not in non-
responders.
Using a different neuroimaging technique, Nakatani et al.
(2003) replicated the nding of decreased activity in the right
caudate nucleus after treatment. The authors used xenon-
enhanced computed tomography (Xe-CT) to study regional
cerebral blood ow (rCBF) in 31OCD patients undergoing
behavioural therapy and 31 healthy controls. Before treatment,
there was higher rCBF in the basal ganglia of patients compared to
controls. After treatment, there was a decrease of activity in the
right head of the caudate nucleus in the responders (n = 22),
compared to their pre-treatment value, that tended to correlate
with improvement in functional status.
While the above studies reported decreased activity in the right
caudate nucleus, the opposite result was also observed in a recent
study (Apostolova et al., 2010). Here, the authors compared the
effects of Paroxetine hydrochloride and CBT on local metabolic rate
of glucose during resting-state in 16 subjects diagnosed with OCD,
and experiencing active symptoms, for a minimum period of two
years (n = 9 treated with CBT; n = 7 treated with Paroxetine).
Following treatment, glucose metabolism increased in the right
caudate both in responders to drugs and CBT relative to non-
responders, and this increase tended to correlate with symptom
improvement. According to the authors, this unexpected increase
in the right caudate nucleus might be due to concomitant
depression symptoms and/or to the large percentage of early-
onset OCD in the present sample. The results of this study were
subsequently replicated by a more recent investigation (Freyer
et al., 2011) in which the authors employed PET in conjunction
with an event-related paradigm to examine 10 OCD patients
before, and after, CBT therapy, in addition to10 healthy controls,
during a probabilistic reversal learning task. Although a whole-
brain analysis corrected for multiple comparisons did not reveal
any signicant effects, a number of differences were detected using
a more lenient threshold (p < 0.001 uncorrected). In particular,
decreased responsiveness of the orbitofrontal cortex and right
putamen, alongside increased activity in the right caudate nucleus,
was observed in patients relative to healthy subjects post-
treatment. Finally, patients with greater clinical improvement
showed smaller activation increases in the pallidal region relative
to those with limited improvement.
Another study using PET and a resting-state paradigm found
different changes in cerebral glucose metabolism after brief
intensive CBT (Saxena et al., 2009). In comparison to 12 healthy
control subjects following treatment, 10 OCD patients displayed
signicant bilateral decreases in thalamic metabolism alongside a
Pharmacotherapy (number of subjects) Waiting list Controls Neuroimaging method
Fluoxetine hydrochloride (9) 4 PET
PET
12 PET
Paroxetine (7) PET
31 Xe-CT
Fluvoxamine (4) fMRI
10 fMRI
SPECT
MRSI
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4 A. Barsaglini et al. / Progress in Neurobiology xxx (2013) xxxxxx
signicant increase in right dorsal anterior cingulate cortex, which,
in turn, was strongly correlated with the degree of improvement in
OCD symptoms. In addition, a signicant decrease in left dorsal
anterior cingulate cortex was found in controls compared to
patients.
Nakao et al. (2005) also investigated the brain activity of 10 OCD
patients before and, after, treatment with either uvoxamine
(n = 4), or behavioural therapy (n = 6), using fMRI. The authors
hypothesized that treatment would have a signicant impact on
frontal activation. To test this hypothesis, each participant was
scanned during performance of a Stroop task and a symptom
provocation task. After treatment, symptom provocation-related
activation in the orbitofrontal, dorsolateral-prefrontal and anterior
cingulate cortices (ACC) decreased signicantly in both groups,
while Stroop task-related activation in the parietal cortex and
cerebellum increased. The decreased activity in ACC is in contrast
with the increased cerebral glucose metabolism reported by
Saxena et al. (2009). This inconsistency might be due to the use of
different experimental paradigms (i.e. resting-state vs. Stroop task
and symptom provocation).
The largest study published so far was carried out by Yamanishi
et al. (2009), who used SPECT in conjunction with a resting state
paradigm to explore the effects of successful 12 weekly CBT on
brain activity in patients with OCD, who were treatment-resistant
to a single serotonin reuptake inhibitor (SRI). Before CBT, no
signicant differences in brain metabolism were observed
between responders and non-responders; in contrast, after
treatment, responders showed a decrease in the left medial
prefrontal cortex (Brodmann area 10) and bilateral middle frontal
gyri (Brodmann area 10). Also, pre-treatment rCBF in the bilateral
orbitofrontal cortex (OFC) was signicantly correlated with
symptom improvement among the responders following CBT.
According to the authors, this might support the hypothesis that
while CBT may result in changes in rCBF in the medial and middle
frontal cortex, pre-treatment activation of the OFC may provide
predictive information on subsequent CBT response. This hypoth-
esis is supported by the recent observation that pre-CBT metabolic
activity in the right pregenual anterior cingulate cortex correlated
with post-CBT change in symptom severity in a group of 8 OCD
patients investigated using magnetic resonance spectroscopy
imaging (ONeill et al., 2013).
In summary, despite inconsistencies in the results possibly due
to the use of different neuroimaging techniques, psychotherapeu-
tic approaches and/or experimental designs, approximately half of
the studies suggest that psychological treatment of OCD results in a
normalisation of the activation pattern, particularly in the
caudate nucleus, and that this effect is most evident in those
patients who show a good response to treatment. In addition, the
results of studies that have compared the effects of psychotherapy
with those of medication suggest that the effects of these two types
of treatment are qualitatively comparable (Apostolova et al., 2010;
Baxter et al., 1992; Nakao et al., 2005; Schwartz et al., 1996).
3.2. Panic disorder
Panic disorder (PD) has been traditionally associated with
neurofunctional alterations in the fear network, involving both
Table 2
Studies on the effects of psychotherapy on brain activity in PD patients.
Study Psychotherapy (number of subjects)
Prasko et al. (2004) CBT (6)
Sakai et al. (2006) CBT (12)
Beutel et al. (2010) Psychodynamic therapy (9)
Kircher et al. (2013) CBT (42)
CBT, cognitive behaviour therapy; fMRI, functional magnetic resonance imaging; PET, positron emission tomography; PD, panic disorder.
Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
limbic and cortical structures (Dresler et al., 2013). For example,
studies investigating PD patients at rest have found a specic
reduction of grey matter in the parahippocampal gyrus (Lai, 2011;
Massana et al., 2003) in addition to reduced functional activation in
frontal (Eren et al., 2003), temporal (Lee et al., 2006) and parietal
(Lai, 2012) regions. In contrast, studies that investigated PD during
the administration of panic-provoking agents have consistently
reported increased activation in the insular cortex (Dager et al.,
1994, 1997). The neurobiological substrates of psychotherapy in
patients with panic disorder have been investigated in four studies
(see Table 2). In the rst one, Prasko et al. (2004) used PET in
conjunction with a resting-state paradigm to examine the impact
of CBT and antidepressants in two groups of 6 patients, all fullling
the DSM-IV criteria for PD. Importantly, patients were assigned to
one of the two treatment conditions in a random fashion. Based on
these cohorts, symptomatology was observed to improve in both
groups with no signicant effect of treatment. Changes in cortical
metabolism for the two treatments were comparable and included
both increases in the right posterior cingulate, left prefrontal, left
temporoparietal and left occipital cortices and decreases in the
bilateral frontal, right temporal and right parietal cortices. These
results were in part replicated by a subsequent study by Sakai et al.
(2006). The authors employed PET in conjunction with a resting-
state paradigm to examine the impact of CBT in 12 PD patients.
After successful treatment, there was enhanced activity in the
prefrontal medial cortex bilaterally as well as decreased activity in
the right hippocampus, left ventral anterior cingulate cortex, left
cerebellum and pons. A methodological limitation of both studies,
however, was the absence of a control group who did not receive
treatment; thus, some of the changes reported may reect
adaptation effects.
While the previous two studies used PET in conjunction with a
resting-state paradigm, a recent contribution employed fMRI
together with an emotional Go/No-Go task, which involved the
presentation of negative panic-specic, alongside matched posi-
tive, and neutral, words (Beutel et al., 2010). This study also
differed with respect to the use of psychodynamic, rather than CBT,
treatment and the inclusion of a control group of healthy subjects
for comparison. Before treatment, patients (n = 9) relative to
healthy subjects (n = 18) displayed greater activation in the left
amygdala and hippocampus in response to negative panic-specic
words; furthermore activation in these regions was negatively
correlated with right lateral prefrontal activation. According to the
authors, the observation of both limbic hyperactivation and frontal
hypoactivation suggests an abnormal functioning of the fronto-
limbic circuit underpinning emotional and behavioural regulation
under threat conditions. After psychodynamic intervention,
differences between patients and controls in this prefrontal-limbic
circuit were replaced by a normalisation of hippocampal activity.
These results are therefore compatible with the hypothesis that the
effects of psychotherapy on brain functioning involve a top-down
regulation of hyperexcitable limbic structures by prefrontal
control system. Further evidence for an impact of psychological
treatment on fronto-limbic interactions comes from a recent
multi-centre investigation which used a fear conditioning para-
digm to examine the effect of manualized CBT in 42 patients with
panic disorder and agoraphobia in comparison with 42 healthy
Pharmacotherapy (number of subjects) Waiting list Controls Neuroimaging method
Antidepressant (6) PET
PET
18 fMRI
42 fMRI
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A. Barsaglini et al. / Progress in Neurobiology xxx (2013) xxxxxx
controls (Kircher et al., 2013). After treatment patients showed
reduced activation in the left inferior frontal gyrus (IFG) which
correlated with symptom improvement; and increased connectiv-
ity between the IFG and regions of the so-called fear network
comprising of the amygdala, insula and anterior cingulate cortex.
While the above results provide some insight into the
neurobiological substrates of psychotherapy in patients with
panic disorder, it is difcult to draw denite conclusions for a
number of reasons. Firstly, the sample size of the majority of
studies was relatively small with one notable exception (Kircher
et al., 2013). Secondly, in order to isolate specic correlates of
psychotherapy, only Prasko et al. (2004) included treatment with
antidepressants and only Beutel et al. (2010) and Kircher et al.
(2013) included a group of healthy subjects for comparison.
Finally, the four studies used different types of psychotherapies for
different time periods, and therefore are not directly comparable.
Nevertheless, the results provide preliminary evidence that,
following psychological intervention, symptom remission in PD
is associated with functional reorganisation within a distributed
network which includes, amongst others, limbic and prefrontal
regions. Only one study (Prasko et al., 2004) compared the effects
of pharmacological and psychological interventions in PD patients,
and showed that the two types of treatment resulted in similar
changes within a distributed fronto-temporo-parietal network.
3.3. Depression
Functional neuroimaging studies of patients with major
depression have consistently reported reduced metabolism in
frontal and temporal regions, the insula and the basal ganglia
(Gelenberg, 2010). These studies have also provided preliminary
evidence that hippocampal metabolism is associated with severity
of depression (Saxena et al., 2001). In contrast to studies
investigating the neurobiological basis of depression, the results
of studies specically examining the neurobiological changes of
psychotherapy in individuals with depression (see Table 3) have
produced inconsistent results. The rst study used PET to measure
glucose metabolic rate in patients during resting-state, and
compared the effect of an antidepressant, Paroxetine, with that
of interpersonal therapy (IPT) (Brody et al., 2001). All the
participants were scanned twice, once at baseline and once at
12 weeks post-treatment administration. The results showed pre-
post decreases in the bilateral prefrontal cortex in patients treated
with Paroxetine and in the right prefrontal cortex in patients who
underwent IPT. In addition, increased metabolism was found in the
left temporal cortex, after both behavioural and pharmacological
intervention. Since at baseline patients had higher metabolism in
Table 3
Studies on the effects of psychotherapy on brain activity in MD patients.
Study Psychotherapy (number of subjects)
Martin et al. (2001) IPT (13)
Brody et al. (2001) IPT (14)
Goldapple et al. (2004) CBT (14)
Siegle et al. (2006) CBT (14)
Kennedy et al. (2007) CBT (12)
Fu et al. (2008) CBT (16)
Dichter et al. (2009) BADT (12)
Dichter et al. (2010) BADT (12)
Karlsson et al. (2010) Short-term psychodynamic psychotherapy (8)
Dichter et al. (2010) BADT (12)
Hirvonen et al. (2010) Short-term psychodynamic psychotherapy (8)
Buchheim et al. (2012) 15 months psychodymic therapy (16)
Yoshimura et al. (2013) CBT (23)
BADT, brief behavioural activation treatment for depression; CBT, cognitive behaviour therapy; fMRI, functional magnetic resonance imaging; IPT, interpersonal therapy; MD,
major depression; PET, positron emission tomography; SPECT, single photon emission tomography.
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5
the prefrontal cortex and lower metabolism in the medial portion
of the temporal lobe than controls, these results suggest that the
effects of psychotherapy in patients with depression may consist in
a normalisation of the activity in these regions that is also
observed, at least in part, after pharmacological intervention.
Goldapple et al. (2004) also reported decreases in prefrontal
activity after a different type of psychotherapy. In this study,
depressed subjects were assigned to either treatment with CBT or
Paroxetine. After CBT intervention, decreases were evident in the
dorsal, medial and ventral prefrontal cortex, in addition to
increases in the hippocampus and in the dorsal cingulate cortex.
In an effort to replicate these ndings, the same team of
researchers also compared the effects of CBT with those of
Venlafaxine (Kennedy et al., 2007). They hypothesized that CBT
would be associated with additional prefrontal decreases, reect-
ing its impact on top-down processing, whereas Venlafaxine
would be associated with subcortical changes, reecting its impact
on bottom-up modulation. Glucose metabolism was measured
before, and after, 16 weeks of intervention with either CBT or
Venlaxane. Decreases in the orbitofrontal cortex and left medial
prefrontal cortex, along with increases in the metabolism in the
right occipital-temporal cortex, were observed in responders to
both therapies relative to non-responders. Of these responders,
only those who received CBT showed increased activity in the
posterior cingulate and thalamus together with decreased activity
in the left inferior temporal cortex. Conversely, only those who
received Venlafaxine expressed increases in the left temporal
cortex and decreases in the posterior cingulate. The authors
concluded that, consistent with earlier reports, response to CBT
was associated with a reciprocal modulation of corticallimbic
interactions, while Venlafaxine engaged additional cortical and
striatal regions previously unreported in neuroimaging investiga-
tions.
In contrast with the above studies, Martin et al. (2001) did not
detect decreases in prefrontal cortex. The study investigated
metabolic changes as measured by SPECT during resting state in 23
subjects assigned to IPT (n = 13) or pharmacological treatment
with Venlafaxine (n = 15). When pre- and post-treatment data
were compared, the Venlafaxine group showed right posterior
temporal cortex and right basal ganglia increases, while the IPT
group limbic right posterior cingulate and right basal ganglia.
Two other PET studies also focused on changes in neurotrans-
mission implicated in the pathophysiology of depression following
short psychodynamic psychotherapy (Hirvonen et al., 2010;
Karlsson et al., 2010). Karlsson et al. (2010) for example compared
the effect of psychotherapy and Fluoxetine on the density
of serotonin 5-HT1A receptors, building on previous studies
Pharmacotherapy Waiting Controls Neuroimaging
(number of subjects) list method
Venlafaxine (15) SPECT
Paroxetine (10) 16 PET
Paroxetine (13) PET
21 fMRI
Venlafaxine (12) PET
16 fMRI
15 fMRI
15 fMRI
Fluoxetine (15) PET
15 fMRI
Fluoxetine (14) PET
17 fMRI
15 fMRI
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reporting a widespread decrease in the density of serotonin 5-
HT1A receptors in the disease (Bhagwagar et al., 2004; Drevets
et al., 1999; Sargent et al., 2000). Specically, patients were
randomly assigned to either pharmacotherapy or psychotherapy,
with the subsequent groups comprising 15 and 8 subjects
respectively. Binding potential (BP) values, representing the ratio
of specic and non-displaceable binding, were estimated using
white matter as reference region (BP is a crucial measure in the PET
studies to measure the density of available receptors (Laruelle
et al., 2002). Although both groups showed comparable symptom
improvement post-treatment, when pre- and post-treatment
values were compared, only those who underwent psychotherapy
showed increased serotonin 5-HT1A binding in several cortical
regions including dorsolateral prefrontal cortex, ventrolateral
prefrontal cortex, ventral ACC, inferior temporal gyrus, insular
cortex, and the angular gyrus. In a subsequent study by the same
group (Hirvonen et al., 2010), the effect of short psychodynamic
psychotherapy and Fluoxetine was compared in patients with
major depression with a specic focus on striatal and thalamic
dopamine D2/3 receptors. Results showed that although both
treatments led to a signicant improvement in symptomatology,
no effects on D2/3 receptor availability in the ventral striatum or
other subdivisions of the striatum were found. Moreover, only
Fluoxetine increased thalamic D2/3 binding, but this increase was
not correlated with clinical improvement. Thus, the study does not
support the involvement of ventral dopaminergic neurotransmis-
sion in the antidepressant effects of Fluoxetine or psychodynamic
psychotherapy. However, statistical power may have been
hindered by the relatively small sample size.
Unlike the above PET/SPECT studies which examined the
cerebral activity of subjects in a resting state, the fMRI studies
published so far measured the neural correlates of psychotherapy
while participants were involved in cognitive tasks (Dichter et al.,
2009, 2010; Fu et al., 2008). Of these, Fu et al. (2008) were the rst,
examining the effect of CBT on brain function during an affective
recognition task in 16 individuals with depression and 16 matched
healthy volunteers. Stimuli consisted of facial stimuli, morphed to
represent three intensities of sadness, and were asked to make a
decision on the gender of the face. Before treatment, patients
relative to controls displayed higher activity in the amygdala and
hippocampus and a lower activity in the anterior and posterior
cingulate gyri, superior frontal gyrus, inferior parietal cortex and
precuneus. After treatment, a signicant normalisation of activity
in all these areas was observed. The authors also found that the
dorsal anterior activity was a predictor of treatment response to
CBT, a nding which has potential translational implications; for
instance, dorsal anterior activity could be used to identify those
individuals who are most likely to benet or not from CBT, leading
to a more effective use of clinical resources.
Dichter et al. also carried out 2 fMRI studies with the same
sample (2009, 2010). The main goal of the rst study (Dichter et al.,
2009) was to elucidate the neural correlates of Brief Behavioural
Activation Treatment for Depression (BATD) during reward
processing in depressed patients. BATD is a structured and
validated psychotherapy designed to increase engagement with
rewarding behaviours and reduce avoidance behaviours (Hopko
et al., 2003). Brain activity was measured in 12 subjects with
depression and 15 healthy controls, while they were engaged in a
Wheel of Fortune task (WOF), a two-choice decision-making task
involving probabilistic monetary outcomes, before and after BATD.
Following the BATD, patients showed increased activity in
structures that mediate responses to rewards, including the
paracingulate gyrus during reward selection, the right caudate
nucleus during reward anticipation, and the paracingulate and
orbital frontal gyri during reward feedback. In contrast, the main
aim of the second study by Dichter et al. (2010) was to identify
Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
baseline fMRI predictors of response to treatment in depression.
Before and after BATD, they scanned patients and matched controls
while they were performing a task requiring cognitive control in
both sad and neutral contexts. The results showed that following
treatment, there was decreased activity in prefrontal structures
including the paracingulate gyrus, the right orbital frontal cortex
and the right frontal pole in response to stimuli presented within a
sad context. In addition, pre-treatment activity in the paracingu-
late gyrus was identied as a signicant predictor of symptomatic
improvement following treatment.
By contrast, another study examining the effect of psychother-
apy on brain function in patients with depression is also the only
one that investigated the effect of long-term psychodynamic
intervention (Buchheim et al., 2012). Sixteen, un-medicated
outpatients with depression who underwent 15 months of
psychodynamic therapy were scanned twice, before and after
treatment, during the presentation of attachment-related scenes
with neutral descriptions alternated with descriptions containing
personal sentences previously extracted from an attachment
interview. The results showed increased activation in the left
anterior hippocampus/amygdala, subgenual cingulate, and medial
prefrontal cortex in patients compared to healthy controls before
treatment, and a reduction in the same areas after treatment.
Furthermore, this normalisation of brain activity was positively
correlated with general symptom improvement. A similar pattern
of normalisation of brain activity associated with symptom
improvement was observed in a recent investigation by Yoshimura
et al. (2013). Here patients relative to healthy controls showed
hyperactivity in the medial prefrontal cortex (MPFC) during self-
referential processing of negative words; however, following
group CBT, there was a normalisation of brain activity in this region
during the same condition.
In summary, despite the heterogeneity of the studies in terms of
neuroimaging technique, psychotherapeutic approach and experi-
mental paradigm employed, the majority of the above results
suggest that psychological treatment of patients with unipolar
depression results in a normalisation of the activation pattern in
fronto-limbic circuitry. Regarding the relationship between the
effects of psychotherapy and medication, their mechanisms seem
divergent based on the results of two independent studies
(Kennedy et al., 2007). To explain these different mechanisms of
action, it has been suggested that while psychotherapy may exert
its effects top-down, targeting mainly frontal cortical regions and
reducing dysfunctional thought processes, pharmacotherapy may
produce bottom-up changes by disengaging ventral and limbic
regions mediating attention to personally relevant emotional and
environmental stimuli (Goldapple et al., 2004).
3.4. Posttraumatic stress disorder
Functional neuroimaging studies of Posttraumatic stress
disorder (PTSD) have reported increased amygdala activation
using a range of experimental paradigms including script-driven
imagery (Rauch et al., 1996; Shin et al., 2004a), trauma-related
stimuli (Liberzon et al., 1999; Pissiota et al., 2002), trauma-
unrelated emotional material (Bryant et al., 2008; Rauch et al.,
2000) and at rest (Chung et al., 2006; Shin et al., 2009). Another
widely reported nding is decreased activation in medial
prefrontal cortex in relation to script-driven imagery (Bremner
et al., 1999; Shin et al., 2004a), trauma-related, and -unrelated,
emotional, and neutral, stimuli (Lanius et al., 2003; Semple et al.,
2000; Shin et al., 1997, 2005). In contrast, detection of
neurofunctional alterations in the hippocampus has been less
consistent (Bremner et al., 1999; Shin et al., 2004b). One example is
the rst study on the effect of CBT on brain functioning in patients
with non-combat-related PTSD (see Table 4) which employed a
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Table 4
Studies on the effects of psychotherapy on brain activity in PTSD patients.
Study Psychotherapy (number of subjects)
Farrow et al. (2005) CBT (13)
Felmingham et al. (2007) Exposure base treatment CBT (8)
Peres et al. (2007) Exposure base treatment CBT (16)
Lindauer et al. (2008) BEP (10)
Roy et al. (2010) VRET (7)
PE (8)
BEP, brief eclectic psychotherapy; CBT, cognitive behaviour therapy; fMRI, functional magnetic resonance imaging; PE, prolonged exposure; PET, positron emission
tomography; PTSD, posttraumatic stress disorder; VRET, virtual reality exposure therapy.
social cognition task (Farrow et al., 2005). The authors hypothe-
sized that PTSD would be associated with altered activation in
brain regions implicated in emotional and social cognition, and
that CBT would have a normalising effect. Thirteen subjects who
satised the DSM-IV criteria for PTSD were examined before and
after CBT, using an experimental fMRI task which tapped into
social cognition of empathy and forgiveness. Symptom improve-
ment was accompanied by an increase of brain activity in the
middle temporal gyrus during empathy judgments and in
posterior cingulate gyrus and left middle frontal gyrus during
judgments of forgiveness.
Similar effects in frontal and temporal regions were also
observed in a subsequent study by Felmingham et al. (2007).
Specically, the authors examined the effect of an exposure-based
CBT in 8 PTSD patients reporting that, pre-treatment, greatest
activation was observed in the right post-central gyrus, right
middle temporal gyrus, and left superior temporal gyrus, whilst
post-treatment, increased activation was found in the left middle
temporal gyrus, right inferior frontal gyrus, left parieto-temporal
gyrus, and right hippocampus. Improvement of symptom severity
was also found to be correlated with increased activation in the
right ACC and decreased activation in the bilateral amygdala. It
should be noted however that both studies employed small
samples and that neither included a control group (comprising
either healthy controls or untreated patients).
Peres et al. (2007) remedied one of these methodological
problems by using for comparison a group of patients who were on
a waiting-list, and therefore currently untreated. Both the
experimental group, which underwent CBT for 8 weeks, and the
waiting-list group was comprised of subjects with sub-threshold
PTSD symptoms which did not full the DSM-IV criteria for PTSD.
The task used was a symptom provocation paradigm, in which
subjects were asked to retrieve traumatic memories while a single
photon emission computed tomography (SPECT) was executed.
After treatment, the CBT group showed an improvement of
symptomatology and experienced emotionally less intense states
during the retrieval of traumatic memories. These improvements
were accompanied by increased activity in the left prefrontal
cortex and decreased activity in left amygdala, which had also been
reported by Felmingham et al. (2007), in addition to further effects
in the parietal lobes bilaterally, left hippocampus and left
thalamus. Positive correlations were also found in the left
hemisphere between the prefrontal cortex and thalamus, and
between the prefrontal and parietal cortices. The authors argued
that activation of the left prefrontal cortex subsequent to CBT
probably indicated better inhibition of feedback processes related
to amygdala activity. This would indicate a normalisation of the
ability to process sensory information, which would enable
subjects to integrate sensorial traces of traumatic memories into
more structured narrative patterns.
Another SPECT study (Lindauer et al., 2008), employed a trauma
imagery paradigm in which the traumatic event chosen was
personalized for each subject. Subject groups included patients
treated with 16 weeks of brief eclectic psychotherapy (BEP), a
Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
7
Pharmacotherapy Waiting list Controls Neuroimaging
(number of subjects) method
fMRI
PET
11 PET
10 15 fMRI
4 PET
treatment that applies both CBT and psychodynamic techniques,
patients on a waiting list and healthy control subjects. Pre-
treatment, the PTSD group (comprising those intended for BEP and
those on the waiting list) showed greater activation compared to
controls in the right insula and right superior/middle frontal gyrus.
Comparatively, post-treatment, the subjects in the BEP group
showed signicant improvement in levels of symptomatology
compared to those on the waiting list, which were accompanied by
a decrease in activation in the right middle frontal gyrus.
Furthermore, improvements in the PTSD symptoms also correlated
positively with activation in the left superior temporal gyrus and
the superior/middle frontal gyrus. The results suggest therefore
that BEP induced clinical recovery in PTSD patients, and appeared
to modulate the functioning of specic PTSD-related sites in the
prefrontal cortical regions.
The most recent contribution to the PTSD literature used fMRI
to investigate the effect of virtual reality exposure therapy (VRET)
and prolonged exposure (PE) on the brains of military members
who had been deployed in Iraq or Afghanistan (Roy et al., 2010).
Pre-treatment, increased activity in the right amygdala and lateral
prefrontal cortex was found, as well as decreased activity in the
ACC. Post-treatment however, the subjects showed a normal-
isation of activity in the same neuroanatomical areas.
Taken collectively, despite a number of inconsistencies which
may be explained by differences in imaging technique, experi-
mental paradigm and patient population, the majority of the
reviewed studies indicate abnormal activity that is evident pre-
treatment in the frontal cortex and in the amygdala, whereas the
effects of treatment seem to affect activity in frontal and temporal
regions specically. However, none of the studies on PTSD
compared the effect of psychological intervention with those of
medication.
3.5. Specic phobia
A number of functional neuroimaging studies have examined
the neurofunctional alterations associated with specic phobia.
The most consistent nding is hyperactivity in the insula (Del
Casale et al., 2012; Linares et al., 2012); however, a number of other
regions have been reported to be hyperactivated in response to
phobic stimuli including the anterior insula, hippocampus, dorsal
and rostral ACC, and somatosensory and occipitoparietal cortices
(Rauch et al., 1995; Wik et al., 1997). So far, a total of six
neuroimaging studies have investigated the neurobiological
changes associated with psychotherapy in subjects with specic
phobia, see Table 5. Two of these studies focussed on social phobia
(Furmark et al., 2002; Goldin and Gross, 2010). Furmark and
colleagues investigated the effects of CBT and Citalopram on rCBF
in 18 previously untreated patients with social phobia during an
anxiogenic public speaking task (Furmark et al., 2002). Symptom
improvement was associated with attenuated activation in the
bilateral amygdala, the hippocampus and the parahippocampal
cortex within both treatment groups, suggesting common sites of
action for psychological and pharmacological treatment. A
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Table 5
Studies on the effects of psychotherapy on brain activity in phobic patients.
Study Type of phobia Psychotherapy (number of subjects)
Paquette et al. (2003) Arachnophobia CBT (12)
Straube et al. (2006) Arachnophobia CBT (13)
Schienle et al. (2007) Arachnophobia CBT (13)
Schienle et al. (2009) Arachnophobia CBT (10)
Furmark et al. (2002) Social phobia CBT (6)
Goldin and Gross (2010) Social phobia MBRS (14)
CBT, cognitive behaviour therapy; fMRI, functional magnetic resonance imaging; MBRS, mindfulness-based stress reduction; PET, positron emission tomography.
strength of this investigation was the inclusion of a group of
patients on a waiting list who showed neither symptomatic nor
neurofunctional changes between baseline and follow-up. More
recently, Goldin et al. examined the effects of mindfulness-based
stress reduction in 16 patients performing an emotional regulation
task (Goldin and Gross, 2010). After treatment patients showed
impoved sympomatology and reduced right amgdala activation,
consistent with the results of the earlier study by Furmark and
colleagues.
The remaining four studies examined patients with arachno-
phobia using functional magnetic resonance imaging and a
paradigm of symptom provocation, via exposure to feared stimuli
pictures or lm (Paquette et al., 2003; Schienle et al., 2007, 2009;
Straube et al., 2006). Paquette et al. (2003) observed that pre-
treatment, arachnophobic subjects showed signicantly greater
activation than healthy subjects in the dorsolateral prefrontal
cortex, parahippocampal gyrus and occipital cortex, however, after
CBT these differences were no longer observed. The authors argue
that these results support the notion that CBT reduces phobic
avoidance by deconditioning contextual fear learning at the level
of the hippocampal/parahippocampal region, and by decreasing
cognitive misattributions and catastrophic thinking at the level of
the prefrontal cortex. However, the study has two limitations
which need to be considered. Firstly, activation in healthy
participants was only examined at baseline; secondly, a group
of phobic subjects not receiving treatment was not included.
The results of Paquette et al. (2003) are inconsistent with a
following study by Straube et al. (2006) however, which also
included a group of phobic subjects on a waiting list to receive
treatment for comparison. At baseline, when viewing a moving
black small synthetic cylinder which resembled a spider, the
phobic subjects showed activation of the insula and anterior
cingulate cortex (ACC) while the healthy subjects expressed
activation of the amygdala. Following treatment, both the patients
who had received CBT and also the healthy control subjects
showed an absence of activation during symptom elicitation in the
ACC and only a small cluster of activation in the ventral anterior
insula, while the waiting list patients still displayed high responses
bilaterally in the insula and ACC. Thus, the post-treatment
activation did not differ between CBT and healthy control groups,
while the CBT group showed a reduction in symptom level and a
decreased activity in the insula and the ACC compared to the
waiting list. Based on this, the authors concluded that increased
activation in the insula and ACC is associated with specic phobia
and that an attenuation of these activations is associated with
successful therapeutic intervention.
The two most recent studies however, conducted by Schienle
et al. (2007, 2009) showed results which differed from previous
studies. In the rst one (Schienle et al., 2007), 26 phobic subjects
were randomly assigned to either a CBT group (n = 12), consisting
of one-session therapy lasting approximately 4 h, or a waiting list
(n = 14). Before treatment, the phobic subjects displayed increased
activation compared to the healthy controls in the amygdala and
Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
Pharmacotherapy Waiting list Controls Neuroimaging
(number of subjects) method
13 fMRI
12 14 fMRI
12 14 fMRI
8 fMRI
Citalopram (6) 6 PET
fMRI
the fusiform gyrus as well as decreased activation in the medial
orbitofrontal cortex (OFC), whilst post-treatment in comparison,
the CBT group showed increased activation in the medial OFC
relative to the waiting list. In a subsequent 6 month follow-up
investigation based on the same patients by the same research
team (Schienle et al., 2009), 10 patients who had received CBT in
the previous study, along with eight non-phobic subjects, were
scanned again, while viewing the same phobic pictures they had
seen in the rst session. Patients showed a clinically relevant
symptom reduction and positive long-term improvement. Com-
paring the rst session with the follow-up session, the activation
increase in the medial OFC was still highly signicant. The authors
concluded that the enduring positive CBT effects are mediated by
functional reorganisation in the medial OFC, a region which is
crucial for the self-regulation of emotions and the re-learning of
stimulus reinforcement associations.
Taken together, the results of these studies indicate that
psychological intervention results in an attenuation of brain
responses within the limbic system (Furmark et al., 2002; Paquette
et al., 2003; Goldin and Gross, 2010), whereas the direction of
changes in the prefrontal cortex has been inconsistent across
studies (Schienle et al., 2007, 2009; Straube et al., 2006; Paquette
et al., 2003). In addition, there is also preliminary evidence for a
common site of action for psychotherapy and pharmacotherapy
within the limbic system, although this conclusion is based on the
results of only one investigation which compared the effect of
these two types of treatment (Furmark et al., 2002).
3.6. Schizophrenia
Functional neuroimaging studies have found evidence that
schizophrenia is associated with regional alterations in a
distributed network that includes the dorsolateral prefrontal
cortex, the anterior cingulate cortex and both lateral and medial
temporal regions (Guerrero-Pedraza et al., 2012; Manoach, 2003;
Minzenberg et al., 2009). In addition, it has been suggested that the
core symptoms of this disorder are best explained in terms of
abnormal interactions between regions; consistent with this
hypothesis, a signicant number of studies have reported
reductions in both structural and functional fronto-temporal
connectivity (Allen et al., 2011; Benetti et al., 2009; Pettersson-
Yeo et al., 2011). Five studies have investigated the neurobiological
changes associated with psychological intervention in subjects
with schizophrenia so far (see Table 6) (Bor et al., 2011; Haut et al.,
2010; Kumari et al., 2011; Penades et al., 2002; Wykes et al., 2002).
Following the observation that schizophrenic patients fail to
activate inferior frontal regions during tasks in which healthy
subjects show such activation, Wykes et al. (2002) aimed to
determine whether cognitive remediation therapy (CRT) could
result in brain activation changes in those regions. Twelve patients
who satised the DSM-IV criteria for schizophrenia were examined
using fMRI during performance of a cognitive task before, and after,
psychological intervention. Six of them received control therapy
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Table 6
Studies on the effects of psychotherapy on brain activity in schizophrenia patients.
Study Psychological intervention
(number of subjects)
Wykes et al. (2002) CRT (6)
Control therapy (6)
Penades et al. (2002) CRT (8)
Haut et al. (2010) CRT (9)
CBSST (9)
Kumari et al. (2011) CBT + TAU (22)
TAU (16)
Bor et al. (2011) CRT (8)
CBSST, cognitive behavioural social skills training; CRT, cognitive remediation therapy; fMRI, functional magnetic resonance imaging; SPECT, single photon emission
tomography; TAU, treatment as usual.
consisting of occupational activities, while the other 6 underwent
CRT, focused mainly on attention/concentration and executive
functions. The study also included 6 healthy volunteers for
comparison. Before intervention, both patient groups, in compari-
son to the control group, had lower activation in prefrontal regions
as measured with fMRI. After treatment the same patient groups
showed increased activation in those regions, with the opposite
effect seen in the control group. In addition, the patient group that
showed a positive response to CRT expressed signicant brain
activation in regions associated with working memory, particu-
larly fronto-cortical areas, post-, relative to pre-, treatment.
A more recent investigation examined a similar hypothesis that
schizophrenia patients who receive cognitive training would show
improved working memory performance and increased activation
in prefrontal regions which are typically altered in this disorder
(Haut et al., 2010). A total of 18 schizophrenia patients were
recruited and split into 2 groups; one group (n = 9) received
computer-based cognitive remediation therapy (CRT) and the
other (n = 9) received cognitive behavioural social skills training
(CBSST). In addition, 9 healthy controls were included in the
investigation but received no treatment. The results showed that,
compared to both patients receiving CBSST and also healthy
controls, patients receiving computer-based CRT increased activa-
tion a distributed network of regions implicated in attention and
working memory, including dorsolateral prefrontal cortex, ACC
and frontopolar cortex.
Bor et al. (2011) also reported increases in frontal activity after
CRT. In this study, 17 schizophrenic patients receiving antipsy-
chotic medication were assigned to either a treatment group
(n = 8) or a control group with no additional treatment. The three
groups underwent two fMRI sessions while they performed a
verbal and a spatial task. Signicant increases were observed in the
left/middle frontal gyrus, cingulate gyrus and inferior parietal
lobule for the spatial task in the patients who received CRT
compared to those who did not. Similar but non-signicant trends
were also observed in the same brain regions for the verbal task.
These results are consistent with those of an earlier study by
Penades and colleagues, who examined the effects of CRT in
schizophrenia patients with a prevalence of negative symptoms
(Penades et al., 2002). Subjects performed an executive function
activation task while a single photon emission computed
tomography (SPECT) was executed. Although after neuropsycho-
logical treatment subjects showed improved cognitive perfor-
mance, changes in brain activity were only signicant at trend level
and pointed towards a reduction of hypofrontality. In this study,
however, statistical power may have been compromised by the
relatively small sample size (n = 8).
The last study is the only one that examined the effect of CBT on
brain function in patients with persistent and distressing positive
symptoms of schizophrenia (Kumari et al., 2011). Specically,
54 patients who satised the DSM-IV criteria for paranoid
Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
9
Pharmacotherapy Waiting list Controls Neuroimaging
(number of subjects) method
6 fMRI
SPECT
9 fMRI
15 fMRI
9 15 fMRI
schizophrenia and 2 for schizoaffective disorder underwent two
fMRI sessions during a task involving implicit processing of facial
expressions denoting both direct and indirect threat. The 56
patients were divided into two groups; 28 patients continued to
receive the usual treatment with antipsychotic medication and 28
patients received CBT for 68 months in addition to their
antipsychotic treatment. The CBT group, but not the other group,
showed decreased activation of the inferior frontal, insula,
thalamus, putamen and occipital areas during the processing of
fearful and angry expressions post-relative to pre-treatment. In
addition, the decrease in activation in these regions was
proportional to symptom improvement.
Taken collectively, the results of these studies suggest that
psychological intervention in patients with schizophrenia results
in a normalisation of activation pattern in the fronto-cortical areas,
particularly a reduction of the hypofrontality which is present
prior to treatment.
4. Discussion
The aim of the present article was to provide a systematic and
critical review of studies on the impact of psychotherapy on the
brain. Based on the studies reviewed, it is clear that psychological
interventions have the potential to modify brain function across a
range of psychopathological conditions. However, the comparison
among studies is made difcult by the employment of different
neuroimaging techniques; for example, the use of PET and fMRI in
the same clinical sample could produce inconsistent results since
the two techniques measure different physiological parameters
(e.g. cerebral blood ow and deoxyhemoglobin concentration) and
vary in terms of their spatial resolution (with a single scan acquired
over 6090 s in PET and a 24 s in fMRI) (Mechelli et al., 2000,
2001). In addition to their difference in sensitivity, both PET and
fMRI have intrinsic potential limitations which require one to
interpret the results of the published studies with caution
(Logothetis, 2008; Racine et al., 2005). The comparison between
the results of different studies is further complicated by
methodological inconsistencies, including, but not limited to,
the type of psychological intervention (e.g. CBT, psychodynamic),
the specic analytical approach taken, the type of control subjects
(healthy, waiting list) recruited, the precise interval between pre-,
and post,-treatment scan, the experimental paradigm (resting
state, activation task), and the inclusion of a control condition. For
example, in a recent investigation involving a group of schizo-
phrenia patients undertaking two fMRI tasks, differential func-
tional alteration was observed relative to a rest condition
depending on the task being compared (Salomon et al., 2011). A
distinction should also be made between studies that used a
symptom provocation paradigm to examine the neuronal corre-
lates of specic symptoms, and those that used resting state or a
cognitive task to characterize the neuronal basis of cognitive
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10 A. Barsaglini et al. / Progress in Neurobiology xxx (2013) xxxxxx
dysfunction. However, it is difcult to draw rm conclusions about
the impact of this methodological variability on the results given
that different experimental paradigms have often been used to
examine different psychiatric disorders; for example symptom
provocation paradigms have been employed in studies of
arachnophobia and PTSD, whereas resting state and cognitive
tasks have typically been used in studies of OCD and schizophrenia.
The interpretation of the results of some of the studies is also
hindered by three further issues, namely, the use of a relatively
small sample size, the lack of information about pharmacological
treatment before, during, and after the administration of
psychotherapy, and the absence of a waiting-list, or a healthy,
control group. However, in spite of these inconsistencies and
limitations, it is possible to identify some trends relevant to the
outlined questions of interest.
With respect to the rst question, whether neurobiological
changes observed post-psychotherapy occur in regions that
showed signicant neurofunctional alteration pre-treatment,
there appears at least two ways in which psychotherapy might
affect the brain (Mechelli, 2010). One possibility is that therapy
might reverse structural or functional abnormalities associated
with a certain psychopathology before therapy; in other words,
psychotherapy might normalise the structure and function of the
brain. The other possibility is that therapy might lead to
compensatory changes in areas of the brain which did not show
altered function before therapy (Mechelli, 2010). In order to
distinguish between these two possibilities, it is necessary that the
brain function of patients be compared against that of healthy
volunteers. Out of the 42 studies reviewed, only 24 included a
control group of healthy subjects; amongst these only a small
faction reported a direct comparison between patients and
controls pre-treatment, although all of them reported the same
comparison post-treatment. Therefore it is not always possible to
establish whether the reported treatment-induced down-, or up-,
regulation corresponds to a normalisation of function. However,
based on those studies that did include a control group, we can
draw some tentative conclusions. The rst of these is that the
impact of psychotherapy on patients with OCD, depression or
schizophrenia appears to result in a normalisation of brain
function. Specically, in the case of OCD, this normalisation
corresponds to a reduction of the metabolism in the orbitofrontal
cortex and the head of the caudate nucleus (Baxter, 1992; Nakao
et al., 2005; Schwartz et al., 1996); in the case of depression, it
involves the fronto-limbic circuitry (Brody et al., 2001; Dichter
et al., 2010; Fu et al., 2008; Goldapple et al., 2004; Kennedy et al.,
2007); and, in the case of schizophrenia it involves fronto-temporal
regions (Haut et al., 2010; Kumari et al., 2011; Wykes et al., 2002).
In contrast, symptom remission in PD and PTSD patients appears to
be associated with compensatory changes in areas not impaired
pre-therapy, with PD itself associated with functional reorganisa-
tion within a distributed network including limbic and prefrontal
regions amongst others (Beutel et al., 2010; Prasko et al., 2004;
Sakai et al., 2006). Results for PTSD are less consistent but indicate
that pre-treatment abnormal activity is most evident in the frontal
cortex and the amygdala, whereas the effects of treatment are
typically detected in frontal and temporal regions (Farrow et al.,
2005; Felmingham et al., 2007; Lindauer et al., 2008; Peres et al.,
2007; Roy et al., 2010). With regard to specic phobia the studies
suggest that the recovery mechanism following psychotherapy
may be mediated by either normalisation of the brain function
which includes limbic and prefrontal regions (Furmark et al., 2002;
Paquette et al., 2003; Straube et al., 2006; Goldin and Gross, 2010)
or a reorganisation in the medial OFC (Schienle et al., 2007, 2009).
Thus, depending on the disorder under investigation, psychother-
apy results in either a normalisation of abnormal patterns of
activity, the recruitment of additional areas which did not show
Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
altered activation prior to treatment, or a combination of the two
(see Fig. 1 for summary).
With respect to the second question, namely, whether
neurobiological changes observed post-psychological treatment,
are similar, or different, to those observed following pharmaco-
logical treatment, possible answers are available from studies of
pathologies where both treatments are commonly used (Linden,
2008). For example, among the studies focussing on OCD, ve
compared the effects of psychotherapy with those of medication.
Of these, four suggest that the effects of the two types of treatment
are comparable (Apostolova et al., 2010; Baxter et al., 1992; Nakao
et al., 2005; Schwartz et al., 1996). However in the remaining study
by Brody et al. (Brody et al., 1998), they reported that patients
responded preferentially to a particular type of treatment
depending on their specic pattern of brain metabolism measured
prior to treatment. In addition, only one study (Prasko et al., 2004)
compared the effects of pharmacological and psychological
intervention in PD patients, and found that both types of treatment
led to increases in the right posterior cingulate, left prefrontal, left
temporo-parietal and left occipital cortices in addition to decreases
in the bilateral frontal, right temporal and right parietal cortices. In
contrast, the mechanisms of medication and psychotherapy with
respect to depression seem to be divergent, or only partly
overlapping. For instance, it has been shown that while CBT
appears correlated with increased activity in the posterior
cingulate and thalamus, together with decreased activity in the
left inferior temporal cortex, treatment with Venlafaxine seems to
be associated with increases in the left temporal cortex and
decreases in the posterior cingulate respectively (Kennedy et al.,
2007). Another study (Martin et al., 2001) also reported that
Venlafaxine group showed right posterior temporal cortex and
right basal ganglia increases, while the IPT group showed increases
in the limbic, right posterior cingulate and right basal ganglia
regions. Furthermore, it has been suggested that whilst psycho-
logical treatment may exert its effects through a top-down
mechanism, targeting mainly frontal cortical regions and reducing
dysfunctional thought processes associated with prefrontal
activity, pharmacotherapy may produce bottom-up changes by
disengaging ventral and limbic regions mediating attention to
personally relevant emotional and environmental stimuli (Roff-
man et al., 2005). However, none of the reviewed studies on phobia
and PTSD compared the effect of psychological intervention with
those of medication and as such the validity of this hypothesis
could not be examined. Taken collectively, these results indicate
that the effects of psychotherapy on brain function are comparable
to those of medication for some but not all disorders.
With respect to the third question regarding whether neurobi-
ological changes could be used as an objective means of monitoring
the progress and outcome of psychotherapy, our review shows that
a number of studies have indeed reported an association between
changes in brain function and symptom improvement following
the administration of psychotherapy (Baxter et al., 1992; Peres
et al., 2007; Prasko et al., 2004; Schienle et al., 2009; Wykes et al.,
2002). Arguably, the results of these studies support the notion
that functional neuroimaging methods could potentially be used to
evaluate the clinical impact of a particular treatment. However,
this conclusion should be made with caution since only a small
fraction of published studies (14%) included a waiting list, and
were therefore able to dissociate between the direct impact of
psychotherapy on brain function and the neurobiological changes
associated with the natural course of the disorder. In addition, it
should be remembered that the primary aim of psychotherapy is to
promote changes in the persons mood, beliefs and behaviour,
rather than the underlying functional changes in the brain. Such
functional changes in the brain have in themselves no obvious
meaning and need to be interpreted with reference to changes in
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A. Barsaglini et al. / Progress in Neurobiology xxx (2013) xxxxxx 11

Fig. 1. This gure shows, for each psychiatric disorder, the overlap between regions that are functionally altered at baseline and regions that have been reported to show
psychotherapy-related changes. ACC, anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; FG, fusiform gyrus; IFG, inferior frontal gyrus; IPL, inferior parietal
lobule; LTC, lateral temporal cortex; MFG, middle frontal gyrus; MPFC, medial prefrontal cortex; MTC, medial temporal cortex; OCD, obsessive-compulsive disorder; OFC,
orbitofrontal cortex; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PFMC, prefrontal medial cortex; PHG, parahippocampal gyrus; PTSD, posttraumatic stress
disorder; SFG, superior frontal gyrus; STG, superior temporal gyrus; vACC, ventral anterior cingulate cortex.

the patients mood, beliefs and behaviour. Thus, the use of
neurobiological changes as an objective means of monitoring the
progress and outcome of treatment still relies on the subjective
reports by the patient and the therapist.
In the current review we focused on the effects of psychothera-
py on brain function since, at present, no studies have examined its
impact on brain structure. This is somehow surprising given that,
over the past decade, a number of studies have shown that the
acquisition of a new skill, such as learning to navigate in a complex
environment, results in structural grey and white matter changes
which can be observed within months or even weeks (Draganski
et al., 2004; Elbert et al., 1995; Maguire et al., 2000; Mechelli,
2010). It is therefore likely that psychotherapy is also associated
with measurable changes in brain structure. This is indirectly
supported by a recent investigation showing that individuals who
practiced mindfulness meditation had increased grey matter
concentration relative to those who did not, and that the size of
the increase was directly correlated with the amount of meditation
training (Holzel et al., 2008).
We note that the studies included in the present review were
performed in a single research centre with only one exception
(Kircher et al., 2013); this means that the number of subjects who
participated in a given study was relatively small and the extent to
which the results can be generalized to the rest of the population is
unclear. For instance, a recent analysis of effect size in classical
statistics has suggested that, in order to optimize the sensitivity to
non-trivial effects, the optimum sample size for a study is at least
16 (Friston, 2012); however, only approximately 19% of the studies
included in our review met this criterion. Future research may
benet from a multi-centre approach involving the integration of
datasets acquired at different research sites using the same
experimental design and acquisition sequence. This approach has
been successfully employed in neuroimaging studies of neurologi-
cal or psychiatric disorders in which subject recruitment is difcult
(Nestor et al., 2008). We also note that the vast majority of studies
reviewed here employed a control group that comprised of healthy
volunteers rather than patients on a waiting list. This means that
some of the changes attributed to the impact of psychotherapy in
these studies may in fact be due to the natural course of the
disorder. A further complication is that patients, particularly those
with anxiety disorders, may nd the experience of being in the
scanner more stressful and may show less habituation to the
scanning environment across multiple sessions compared to
healthy volunteers. This may result in higher degree of head
movement in patients than healthy volunteers thereby introducing
a systematic bias in the data (Power et al., 2012). In order to
minimize these potential confounds, future research would benet
from the inclusion of two control groups comprising of patients on
a waiting list and healthy volunteers respectively; this would also
allow one to distinguish between longitudinal changes in brain
function due to psychological treatment and those associated with
the natural course of the illness. Finally we note that all studies
published so far reported average differences between different
groups (e.g. responders versus non-responders); the translational
impact of these ndings in real-life clinical practice is limited
because clinicians need to make decisions about individual
patients rather than groups. The clinical utility of the results
could be enhanced by the application of novel analytical methods
based on machine learning theory, such as Support Vector Machine
(Orru et al., 2012) and Gaussian Process Regression (Marquand

Please cite this article in press as: Barsaglini, A., et al., The effects of psychotherapy on brain function: A systematic and critical review.
Prog. Neurobiol. (2013), http://dx.doi.org/10.1016/j.pneurobio.2013.10.006
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PRONEU-1305; No. of Pages 14
12 A. Barsaglini et al. / Progress in Neurobiology xxx (2013) xxxxxx
et al., 2010), that allow inferences at the level of the individual
rather than the group. For example, it might be possible to apply
machine learning techniques to neuroimaging data to predict the
impact of different psychological treatments in a given patient, and
use this information to develop personalized interventions
(Costafreda et al., 2009).
A limitation of the present review is that we adopted a
qualitative evaluation of the literature rather than a quantitative
meta-analytic approach; this was motivated by the small number
and the methodological heterogeneity of the studies published so
far for each psychiatric disorder. For example, although resting-
state was the most common experimental paradigm, this was used
in approximately 20% of the published studies. Future studies will
benet from the use of a more consistent methodological
approach, which will eventually enable meta-analytic reviews.
In summary, the nding of a measurable impact of psychother-
apy on brain function provides the basis for future investigations
that could have translational implications for clinical practice.
Firstly, it would be of signicant interest to examine whether
changes in brain function in the early stage of treatment are
predictive of long-term response to psychological therapy, with
such information potentially being used to inform early clinical
intervention for a given patient. Secondly, a deeper understanding
of the neurobiological mechanisms underlying symptom improve-
ment could inform the development of new effective treatments,
for instance, neuro-feedback, in which brain signals could be used
as a feedback for patients to alter their dysfunctional psychopath-
ological states through self-regulation of cortical activity
(deCharms et al., 2005). Thirdly, it would be interesting to re-
examine patients several weeks, months, or even years after the
end of their treatment in order to assess whether, and to what
extent, therapy-induced changes are long-lasting. Fourthly, the
studies reviewed here typically focused on treatment-induced
changes in regional activation; only one recent investigation of
panic disorder examined the impact of treatment on the functional
connectivity between regions (Kircher et al., 2013). However, a
number of psychiatric disorders are characterized by poor
functional integration within distributed networks (Pettersson-
Yeo et al., 2011), and it follows that the effects of psychotherapy
and medication are likely to be expressed also in terms of changes
in functional integration amongst the different regions (Friston,
2004). A characterization of the effects of treatment in terms of
changes in functional or effective connectivity may allow greater
sensitivity and provide new insights into the neurobiology of
psychological recovery. Despite the potential of the above lines of
research, it is important to acknowledge that neuroimaging
techniques have intrinsic limitations that may hinder the
translational value of such results. For example, signicant effects
represent relative differences which are highly dependent on the
experimental conditions being contrasted, the type of preproces-
sing applied to the images and the analytical technique employed
to make statistical inferences. In conclusion, the question of
whether psychological intervention can lead to measurable
changes in the brain seems beyond doubt. However, the impact
of psychological treatment appears to be highly dependent on the
disorder under investigation and the type of therapy employed. It
is hoped that the results will eventually inform the development of
new biologically informed treatments which will allow clinicians
to make more effective treatment decisions in everyday clinical
practice.
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