Epigenetics and Psychotherapy

Hindawi
Psychiatry Journal
Volume 2017, Article ID 5491812, 38 pages
https://doi.org/10.1155/2017/5491812
Review Article
Epigenetic and Neural Circuitry Landscape of
Psychotherapeutic Interventions
Christopher W. T. Miller
University of Maryland School of Medicine, 701 W. Pratt St., 4th Floor, Baltimore, MD 21201, USA
Correspondence should be addressed to Christopher W. T. Miller; [email protected]
Received 10 December 2016; Accepted 11 April 2017; Published 25 May 2017
Academic Editor: Vaishnav Krishnan
Copyright © 2017 Christopher W. T. Miller. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
The science behind psychotherapy has garnered considerable interest, as objective measures are being developed to map the patient’s
subjective change over the course of treatment. Prenatal and early life influences have a lasting impact on how genes are expressed
and the manner in which neural circuits are consolidated. Transgenerationally transmitted epigenetic markers as well as templates
of enhanced thought flexibility versus evasion can be passed down from parent to child. This influences gene expression/repression
(impacting neuroplasticity) and kindling of neurocircuitry which can perpetuate maladaptive cognitive processing seen in a number
of psychiatric conditions. Importantly, genetic factors and the compounding effects of early life adversity do not inexorably lead
to certain fated outcomes. The concepts of vulnerability and resilience are becoming more integrated into the framework of
“differential susceptibility,” speaking to how corrective environmental factors may promote epigenetic change and reconfigure
neural templates, allowing for symptomatic improvement. Psychotherapy is one such factor, and this review will focus on our
current knowledge of its epigenetic and neurocircuitry impact.
1. Introduction equivalence [1, 2], has garnered considerable controversy [3],

but on a neuroscientific level there may be some value to it,
The effects of psychotherapy from a clinical perspective are given that much of what has been shown as the effects of
growing in evidence base, particularly given the desire within continued psychotherapeutic action has been activation of
the scientific community to translate concepts which many more interpersonally attuned areas of the brain, as well as
times are subjective and abstract into demonstrable and greater expression of genes allowing for plasticity in areas
replicable effects. This has gained substantial ground recently, involved with higher cognitive processing and with fine-
as the benefits of psychotherapy have been demonstrated on tuning the activity of subcortical areas. Neuroendocrine and
multiple levels, including its epigenetic, neurocircuitry, and neurocircuitry templates established early in life will be the
neuroendocrine influences. Also, animal models have shown default manner of negotiating environmental stimuli, and
the benefits of continued environmental enrichment (EE) conditioned responses, especially as they pertain to interper-
on psychopathological phenotypes, which carries exciting sonal models of interacting, will arise within the therapeutic
translational value, particularly given that some of these dyad (i.e., the therapist and patient). Assessing the patient’s
studies utilize animals which are genetically bred to exhibit symptomatology and personality structure in light of early
maladaptive phenotypes. Thus, the environment can con- life experience has been enriched by research investigating
tinue to influence behavioral paradigms throughout the life how their individual make-up came to be, and reshaping of
cycle. The premise of most forms of psychotherapy highlights endocrine responses and select activation of certain neural
the importance of the therapeutic alliance and the devel- networks, in particular when faced with life stressors, is a
opment of a rapport that feels containing for the patient. powerful indicator of therapeutic response. This paper will
Indeed, the “Dodo Bird Verdict,” positing that in the end all aim to outline how early life experience lays down this
forms of psychotherapy have some degree of empirical template, which in many ways is enduring and very difficult to
2 Psychiatry Journal
undo, and how the environment factors can foster significant associated with amygdala hyperreactivity and altered threat
change throughout one’s life. processing [17]. Also, elevated levels of norepinephrine and
dopamine have been associated with greater externalizing
2. Prenatal and Early Life Influence behaviors and aggressiveness [18], more pronounced when
immersed in a threatening and unpredictable environment.
Most central nervous system (CNS) neurogenesis occurs over Importantly, MAO-A is an X-linked gene, and males carrying
a period spanning just over two years, and most telencephalic a hypoactive allele may have in effect a knockout gene.
neurons are generated before birth [4]. Contingent and Another vulnerability gene is the Solute Carrier Family
appropriate responses from the infant’s primary caregiver 6, member 4 (SLC6A4), which codes for the serotonin trans-
are crucial in facilitating CNS development, and the more porter (5-HTT or SERT). The short (s) allele of the serotonin
interpersonally attuned right hemisphere shows a more accel- transporter-linked polymorphic region (5-HTTLPR) has
erated growth during the late fetal and early postnatal periods been associated with later development of psychopathology
[5, 6]. Attunement to the child also informs how he or she will (in interaction with an adverse environment), in particular
internalize the model for social interactions; early life neglect major depressive disorder (MDD), suicide attempts, anxiety
and abuse can lead to a plethora of psychiatric and somatic disorders, and attention-deficit and hyperactivity disorder
conditions, including growth delays, immune dysregulation, (ADHD) [16, 19, 20]. From early on, maternal sensitivity may
low levels of oxytocin, and impairment in social reciprocity allay some of the negative emotionality in children showing
[7–10]. Thus, the “psychobiologically attuned caregiver” has a the s allele, demonstrating the interplay with the environment
pivotal role in regulating an infant’s brain development [11]. In [21]. The s allele (coding for a hypofunctional serotonin trans-
ideal situations, the caregiver will be attuned to the child and porter) would impair reuptake of serotonin into the presy-
able to provide comfort during distressing states, something naptic terminal, increasing availability of this neurotransmit-
which will allow for the child to emerge with a basic sense of ter in the synaptic cleft. In addition to the effect on amygdala
safety and trust, in particular as motor skills are furthered and reactivity highlighted above, it is noteworthy that the seroton-
exploration of the world is the next task to face, something ergic system is closely linked with functionality of inhibitory
which may be exciting or terrifying. GABAergic systems (particularly with regard to prefrontal
cortex-basolateral amygdala connectivity, mediated through
2.1. Genetic Considerations GABAergic intercalated cells), additionally informing how
fear modulation and threat processing will take place during
2.1.1. Vulnerability Genes. Genetic vulnerability is a topic life [22]. Animal models of knockout groups for the SERT (in
of some controversy, particularly as we learn more about an attempt to replicate the effects of the s allele) have shown
the complex interaction between an individual’s genetic that the amygdala is primed for aversive conditioning, given
endowment and how the environment influences expression. the decrease in 5-HT1A sensitivity [23] and an increase in
A number of genes which have been termed “vulnerability 5-HT2C expression [24], serotonin receptor subtypes which
genes” have been identified and replicated in human studies are anxiolytic and anxiogenic, respectively. It is important
as conferring a particular risk of psychopathology. The to underscore that these are far from negligible genetic
counterpoint to this will be presented later in the paper, vulnerability markers; for instance, the prevalence in the
underlining concept of “differential susceptibility” [12, 13], a general population of the s allele of SERT is around 43% [19]
hypothesis which posits that there is varying susceptibility of and that of a hypofunctioning MAO-A allele is approximately
individuals to the effects of the environment depending on 29% [25].
genetic make-up. As such, some individuals would display High-induction single nucleotide polymorphisms (SNPs)
worse outcomes in negative environments but flourish more of the FK506 binding protein 5 (FKBP5) gene (see discussion
in positive environments, highlighting the “plastic” nature below in Section 2.1.2) have been associated with higher glu-
of their responses [14]. The genes that will be discussed in cocorticoid receptor (GR) resistance and hence greater circu-
this paper are primarily those upon which psychotherapy lating cortisol levels secondary to a reduced negative feedback
has been shown to have an impact. Caspi et al. outlined loop. Given higher baseline cortisol, an individual may have
two particular genes in groundbreaking studies which high- more difficulty recovering from a psychosocial stressor, as
lighted one’s susceptibility to behavioral and emotional dys- well as more enduring symptoms during this recovery period
regulation, when coupled with an adverse early environment [26]. Studies have associated these SNPs with a higher
[15, 16]. The first of the studies was performed in human prevalence of MDD [27] and suicide attempts [28], both in
subjects of both genders (with a sample of roughly 1,000 interaction with environmental adversity. The brain-derived
individuals), following them across multiple time points neurotrophic factor (BDNF) Val(66)Met carriers also show
throughout their lives, and demonstrated that a low- an environmentally informed change in circulating BDNF
functioning allele of monoamine oxidase A (MAO-A) was levels, with lower concentrations being found in individuals
associated with numerous adverse outcomes later in life, who have suffered childhood abuse [29].
relating particularly to conduct disorder, antisocial person- The following section will discuss epigenetic modifica-
ality disorder, violence, and incarceration [15]. As MAO-A is tions which can occur with adverse environmental exposure;
responsible for the breakdown of serotonin, norepinephrine, synergistic effects of genetic along with epigenetic changes
and dopamine, suboptimal functioning can lead to an excess may lead to subsequent psychopathology, as will be explored
in neurotransmitter availability. An excess of serotonin can be further.
Psychiatry Journal 3
2.1.2. Epigenetic Changes. An exhaustive review of epigenetic GRs (including those located in the hippocampus) and
changes associated with early life adversity is beyond the demethylation of the FKBP5 gene have been implicated in
scope of this paper. There are comprehensive reviews which the response to stress [41], and these can lead to persistently
can detail DNA and histone changes and nontranscribing elevated cortisol levels. Maternal stress during pregnancy
RNAs, as well as their effects on psychopathology, in much can induce placental gene methylation of FKBP5 and of 11-
greater detail [30, 31]. Given its focus in recent psychotherapy beta-hydroxysteroid dehydrogenase 2 (the latter involved in
research, DNA methylation will be the primary point of dis- inactivating glucocorticoids) [42]; this has an adverse impact
cussion with regard to epigenetics. Gene methylation serves a on fetal coupling, a correlation between the fetus’s heart
repressive function, as it leads to a tighter coiling of the chro- rate and motor activity and an indicator of nervous system
matin, decreasing expression by blocking access of transcrip- development. What seems to be the evolutionarily “adaptive”
tion proteins to the specific sequences. Methylation primarily message from the parent to the child is that the world is a place
occurs on cytosine nucleotides, forming methyl-cytosine. that needs to be considered dangerous, and as such the child’s
Despite a genome-wide wave of demethylation which takes neuroendocrine system is primed to react to its environment
place after fertilization, a number of methyl groups still in such a way. In a study of Holocaust survivors [43],
remain in the DNA by action of the methyl maintenance FKBP5 was shown to be hypermethylated in survivors and
transferases. This allows for inheritance of epigenetic changes demethylated in their offspring. Trauma disorders can be
from parent to offspring [32], a phenomenon which can associated with low cortisol levels, which would in theory
be correlated with subsequent behavioral patterns and psy- allow for norepinephrine to be released excessively without
chopathology. Methylation per se is necessary for maintain- the opposing effects of the glucocorticoid, accounting for the
ing neuronal structural integrity; methylation enzyme knock- characteristic symptom spectrum, with heightened alertness
out has been shown in animal models to cause profound and intrusive reexperiencing [44]. However, what is passed
intellectual disability [33]; experimental models in human down to the infant is an epigenetic modification which would
embryonic stem cells show that deletion of DNA methyltrans- allow for increased cortisol from early on, again emphasizing
ferase 1 (DNMT1) resulted in rapid cell death due to DNA that the child should be prepared for trauma and, seemingly
damage and G1 cell cycle arrest, being thus incompatible with reinforcing the self-kindling cycle, parental trauma has been
life [34]. In addition to its regulatory function, gene methy- associated with subsequent trauma in their offspring [45].
lation can also be an epigenetic marker of trauma [35] and Methylation of genes impacting neurotransmitter sys-
may affect a wide range of neuroendocrine and neurotrans- tems has also been described. In a rat model, early life
mitter systems, as well as informing later psychopathology. adversity can lead to methylation of the glutamic acid decar-
How transgenerational methylation impacts offspring is the boxylase 1 promoter (GAD1) [46]; this enzyme is responsible
subject of much current research effort. It has been displayed for conversion of glutamate to gamma-amino butyric acid
in animal models regarding fears of certain odors [36]; in (GABA); thus, gene repression would lead to a relative excess
the cited study, aversive conditioning to acetophenone was of glutamate relative to GABA; glutamate serves a vital role
induced in F0 mice. Offspring of these mice demonstrated in the normal development of synapses, and excess levels
enhanced sensitivity to this odor, as indicated by an odor- can lead to elimination of nonredundant circuits, particularly
potentiated startle response. There was a significant increase during the perinatal period. In addition, there may be
in populations of olfactory sensory neurons which detect methylation of genes which underlie expression of N-methyl
this odor, as well as hypomethylation of the gene (Olfr151) D-aspartate (NMDA) receptor subtypes [47]; NMDA subunit
responsible for transcribing the particular acetophenone- switch is fundamental for consolidation of synapses and thus
sensitive receptor (M71), with increased genetic and receptor of long-term memory [48], and this may be impaired in
expression. Another study showed that male mice exposed to the event of adverse experiences. Furthering this argument,
unpredictable maternal separation early on later developed the BDNF gene has also been shown to suffer epigenetic
anxiety and depressive-like behaviors, as well as impairment changes in response to childhood adversity. Given the affinity
in social functioning; these phenotypes were later observed of methyl groups for cytosine, it is of particular interest that
in their offspring, even in circumstances of adequate mater- the BDNF gene is rich in cytosine-guanine (CG) islands, and
nal care [37, 38]. While human infants exposed to severe methylation of this gene can persist into adulthood [49]. This
neglect have shown widespread patterns of hypermethylation can influence neurogenesis throughout the life cycle, as well
detected in blood cells [39], a number of key genes involved in as showing an association with later pathology; BDNF gene
the regulation of the stress response and of neurogenesis can methylation has been associated with completed suicides
be affected by early life adversity. The following discussion [50] as well as with development of borderline personality
will highlight some of these genes and the implications of disorder (BPD) [51].
their epigenetic modifications. Further discussion of the mother-child dyad will be pre-
FKBP5 is a cochaperone which, along with heat shock sented later, in particular as it relates to neural circuitry for-
proteins, facilitates transportation of cortisol to the nucleus, mation and strengthening of particular networks depending
where it exerts effects on gene transcription. The function on the level of attunement. Oxytocin is a neuropeptide which
of FKBP5 is to increase the resistance of the GR to cortisol, is involved with social affiliation, maternal behavior and trust,
in effect increasing levels of the latter. An excessive amount bonding, and ascribing salience to social cues [52]. Early life
of cortisol may have a cytotoxic effect, triggering the apop- stress may lead to low levels of oxytocin in the cerebrospinal
totic cascade [40]. Indeed, epigenetic methylation of the fluid (CSF) of women [53], thus potentially impairing the
bonding process with her infant; rodent models have also abbreviated as SHP). During the human infant’s develop-
demonstrated a decrease in oxytocin receptors (OXTR) in the ment, this corresponds roughly to the first 12 months of life
brain when exposed to conditions of suboptimal nurturing [69]. This is a crucial period for attachment, and premature
[54]. Despite low levels of oxytocin and of OXTR gene activation of the amygdala during this time can occur with
expression having been linked with adverse outcomes (e.g., early life stress and subsequent stimulation of the HPA axis
autistic traits and elements of psychopathy) [55, 56], they and secretion of cortisol, as GRs can become activated when
are not unidirectionally and inextricably associated with they should adaptively be blocked. Importantly, the effects
psychopathology [57, 58], and the mediating effect of the of this premature activation can have long-lasting effects
environment has been demonstrated in recent studies. Dif- on the neuroendocrine response [70]. Thus, in the event
ferential susceptibility may factor into this mediating effect, of an abusive caregiver, even though non-amygdala-related
as higher expression of OXTRs may increase an individ- attachment circuitry (much of which involves olfactory
ual’s capacity for empathy [59] but may also predispose to circuits and noradrenergic pathways) would draw the child
greater sensitivity to negative environmental effects, with, for closer to the caregiver, the early conditioning of the amygdala
due to premature plasticity owing to elevated cortisol levels
instance, higher risk for separation anxiety and disorganized
may label this caregiver as dangerous. This creates the
attachment [60, 61]; excessive levels of oxytocin may also
confusing picture of attaching to destructive caregivers in a
cause greater stress sensitivity, as there is an association with disorganized/approach-avoidance manner, a template which
higher risk of anxiety disorders [57]. SNPs within the OXTR can become activated later in life and reenacted in adult rela-
gene do not necessarily lead to adverse outcomes on their own tionships. The SHP has an interesting correlation with Erik
and indeed may be adaptive when dealing with adverse Erikson’s first stage of development, “Trust versus Mistrust”
situations (e.g., the SNP rs53576, a guanine to adenine sub- [71], lasting from zero to 12 months of age, and lining up
stitution, may confer resilience in G/A and A/A individuals with the child’s greater acquisition of motor skills as well as
in the development of psychopathology when faced with the time around which the maternal “blockade” of GRs is
stressful circumstances, as compared to G/G individuals) normally lessened. At this time, conditioned responses to the
[62]. However, there are several SNPs (and associated CpG environment will come more to the fore (as the amygdala is
site methylation patterns) which can interact with abuse to allowed to become plastic through its response to cortisol),
increase the occurrence of anxiety and depressive symptoms with the child’s preceding experience greatly influencing
(though significance is variable) [58, 61, 63]. These associ- whether the template of the world to be discovered will be
ations are clearly complex, and optimal levels of oxytocin imbued with a predominantly positive or negative valence. It
are instrumental in mitigating amygdala and brainstem is of note that, through influence of the basolateral amygdala
hyperactivity in the fear response [64]. Thus, genetic and (BLA), memories that are high in emotional content will be
epigenetic factors impacting its effects are of importance encoded in a more efficient manner than emotionally neutral
when considering subcortical circuitry activation in a child’s experiences [72], adding to the significance of how one’s early
development, as it is informed by the early environment and affective responses are consolidated.
factors into later psychopathology. As a manner of providing contextual and spatial data
to an individual’s experiences, the hippocampus (associated
2.2. Neural Circuitry Formation. Cortisol is produced in primarily with episodic memory and contributing to exec-
the zona fasciculata of the adrenal and is released as utive functioning) can aid in decreasing activation of the
part of the adaptation to stressful circumstances, working amygdala [73], countering (based on experience) the primar-
in tandem with norepinephrine to allow for an adaptive ily salience-based amygdala response. The amygdala, partic-
response to a given situation. Secretion is regulated by the ularly in cases of hyperactivation when faced with stimuli
hypothalamus-pituitary-adrenal (HPA) axis, and circulat- which are sensed to be dangerous, can inhibit the hippocam-
ing cortisol provides negative feedback to block proximal pus as well, blocking access to contextual memories which
release of corticotropin-releasing hormone (CRH) from the could allay fear-based responses. This is relevant, for instance,
hypothalamus. While the amygdala has been shown to in posttraumatic stress disorder (PTSD), as the reexperienc-
become active very early on in life [65, 66] and conditioned ing component heightens one’s reactivity, creating an inflex-
positive and negative responses to stimuli occur from an ible and conditioned reaction to situations removed from
early age, activation is contingent on the presence of cortisol the original traumatic event [74], with impaired access to
(the amygdala is rich in GRs) [67]. Indeed, during the stress hippocampal contextual input which could allow for a more
response, there is a reciprocal loop between the HPA axis informed and less reactive response. From an early devel-
and amygdala, as the latter stimulates release of CRH and opmental perspective, this becomes highly relevant given
can further increase cortisol levels [44]. However, prior to the the infantile amnesia phenomenon, which has posited that
amygdala becoming activated, there is a period during which early memories (prior to around age four years) [75] will be
the presence of the mother effectively “turns off” the GRs erased by subsequent ones within the hippocampal circuitry
in the amygdala, thus blocking its activation by circulating (though it has been recently suggested that there may be
cortisol, something which has been shown in rat pups [68] mnemonic traces which could be subsequently activated)
and which has applicability to humans as well. This is termed [76]. Given the earlier and later consolidation of amygdala
the stress “hyporesponsive” or “nonresponsive” period (here and hippocampal nuclei, respectively, an individual can
attribute strongly positive or negative salience to environ- dictating how one will negotiate future experiences. There
mental components but not have access to hippocampal is also a functional coupling between the amygdala and the
function as a manner of creating some “perspective” on orbitofrontal cortex (OFC) [86], an area of the brain associ-
the situation. This may be internalized as a template and ated with reward and punishment considerations regarding a
default response to situations which may be very difficult to particular setting; thus, the affective salience informed by the
modify based on later experience, particularly if subsequent amygdala is paramount in the approach-avoidance paradigm
environmental factors are adverse as opposed to nurturing. underlying behavioral output. This amygdala-OFC connec-
Certain conditions (e.g., BPD, anxiety disorders, and MDD) tion will create associations of neutral objects with natural
which show preferential activation of the amygdala over the reinforcing or punitive salience [87]. Much of the circuitry
hippocampus may be characterized by all-or-none thinking, discussed will underlie immediate situational responses and
indicating a more crystallized conditioned response. The may result in impulsivity and limited flexibility to deal with
neural correlates of these conditions will be expanded upon novel or complex scenarios.
later. Importantly, even when information is being integrated Subcortical circuitry will connect with higher corti-
into the hippocampus, it may be distorted by the emotionally cal areas and, depending on the hippocampus-amygdala-
driven response informed by the amygdala, leading to faulty hypothalamus output, more “cognitive” or “affective” areas
processing during information compression from the dentate may be preferentially activated as a form of adapting to the
gyrus to layer CA3 [77], both areas which have shown subcortical feedback (Figure 1). The prefrontal cortex (PFC)
decreased volume in childhood abuse [78]. will function to negotiate more complex social behaviors
BDNF is pivotal in promoting hippocampal neuronal through connections with the default brain circuitry; this
survival and plasticity [79]; activation of this growth factor may be done in more or less flexible manners, depending on
throughout the lifespan has been linked with postmitotic which cortical pathways are activated. The anterior cingulate
neurogenesis within the hippocampal dentate gyrus. There cortex (ACC) is an important intermediary in bridging areas
is a close correlation between levels of glucocorticoids and involved in emotional processing with those involved in
BDNF, a balance which is necessary to allow for consolidation more nuanced cognitive functions. It will monitor error and
of learning [80]. However, excessive levels of glucocorticoids conflict, as well as assessing the motivational and emotional
will lead to synaptic loss and suppress the release of BDNF, relevance of stimuli, and thus predict the potential value of
decreasing plasticity in several brain regions including the rewarding or punishing situations and being able to weigh
hippocampus, as the latter is rich in GRs. The importance of different courses of action as informed by this input [88]. As
this lies in the negative feedback the hippocampus provides to alluded to above, there are two main cortical subdivisions
the HPA axis, blocking release of CRH and curtailing further which can be preferentially activated depending on feedback
release of cortisol downstream. For this to happen in a bal- from the ACC. The ventral (“affective”) subdivision regulates
anced manner, the hippocampus needs to express sufficient autonomic/visceral responses to stress, as well as contributing
GRs for this feedback loop to occur. Illuminating studies have to the valence one assigns to a particular stimulus. This
shown that early life adversity can lead to a paucity of GRs on subdivision is composed of the rostral ACC (rACC), sub-
the hippocampus, thus hindering the feedback mechanism genual ACC (sgACC), and ventromedial prefrontal cortex
and leading to elevated levels of cortisol. Rodent models have (vmPFC). The anterior portions of the ACC have connections
shown that mothers that provide less licking and grooming with subcortical areas associated with instrumental responses
(LG) to their pups will result in the latter having reduced to situations, such as the amygdala, brainstem nuclei, and
hippocampal GR RNA (with fewer expressed receptors), periaqueductal gray (PAG); there are also connections with
elevated levels of cortisol (due to impaired negative feed- brain areas involved with reward and risk considerations,
back), decreased BDNF levels, and consequent reductions such as the NAc and the OFC [89]. These portions of the
in hippocampal plasticity, as excess cortisol is neurotoxic, PFC and cingulate cortex are key in the top-down control
as mentioned [49, 81–84]. Thus, the destructive loop per- of limbic activation and thus emotional control. Both the
petuates itself, as the hippocampal neurogenesis is impaired ACC and vmPFC have connections with the amygdala and
due to high circulating cortisol, and the HPA axis is further are activated during the process of fear extinction [90–92];
kindled by a lack of feedback. Early life adversity has also been due to this connection, the vmPFC can allow for a more
associated with an increase in BDNF in the BLA, promoting informed cognitive appraisal of stimuli and aid in controlling
conditioned changes which may be more resistant to mod- the subsequent activation of the amygdala. In particular, the
ification later in life [85]. As such, BDNF can have circuit- connection between the vmPFC and the OFC will help in this
specific effects depending on the area involved, dampening or process of guiding behavior in the context of emotional input
consolidating negative effects of stress (the reader is referred and coding one’s emotional and motivational values [93, 94],
to Section 3.1. for a discussion of the prodepressant effects which will integrate on a more conscious level the approach-
of BDNF release from the ventral tegmental area (VTA) to avoidance templates discussed previously. Importantly, areas
the nucleus accumbens (NAc) in chronic stress paradigms). of the affective subdivision are also involved with empathic
Thus, there can be a predominance of affective or contextually attunement and theory of mind (along with other areas
driven default responses to given situations, depending on such as the temporoparietal junction and the superior tem-
the amygdala/hippocampus balance, and the memory and poral sulcus) [95–97]. This will factor into later discussion
affective salience are internalized in association with individ- regarding the effects of psychotherapy and the fundamentally
uals and circumstances, generating conditioned templates, interpersonal nature of therapeutic action.
Sensory stimuli
Downstream release of cortisol
and monoamines
Information regarding
stimuli valence Amygdala activation: attribution
of positive or negative salience to 4 5
stimuli
2
Hypothalamus: input to
Orbitofrontal cortex: risk and Reciprocal inhibitory pituitary/adrenal axis and
3 input
reward considerations activation of brainstem nuclei
based on threat estimation
Information regarding Hippocampal activation:

episodic experience contextual data input 4
with stimuli
(a)
FC FC
dlP dlP
dor Cingulate dor Cingulate
ros ros
V Vm
PFmC sg PFC sg
OFC HC OFC HC
Am Am
(b)
Figure 1: Depiction of the subcortical-cortical communication which will inform whether the dlPFC or vmPFC will be preferentially activated
in response to environmental stimuli. (a) shows how, as the individual perceives an element in the environment (the thalamus is not portrayed
in this figure), the amygdala will be activated, and positively or negatively valenced associations will emerge based on past experience. The
hippocampus will provide some level of contextual data based on episodic memory, and the OFC will weigh risk and reward considerations
based on input from these two structures. Subsequent neuroendocrine responses will ensue, with the hypothalamus being more or less driven
to initiate downstream cortisol release, as well as stimulating brainstem nuclei for release of monoamines, depending on the subjective sense
of danger felt to be present. (b) illustrates the subsequent higher cortical level activation that will occur after this initial communication. The
subcortical-cortical connection will be mediated by the ACC (either ventral or dorsal portions), which will divert activation preferentially
towards the dl or vmPFC. Left panel: in instances of lower perceived environmental threat, the vmPFC is activated via portions of the sgACC
and the rACC; there is greater inhibitory connection with the amygdala, thus allowing for greater top-bottom mitigation of the fear response
(also aided by the inhibitory contextual hippocampal input); more robust development of the vmPFC-amygdala and hippocampus-amygdala
control mechanisms can allow for more controlled responses to the environment, even when there may be potential threat, as cognitive
control and contextual data will prevent excessive reactivity and stimulus generalization, permitting greater flexibility and hence more
adaptive responses. The vmPFC has been shown to be hypoactive in cases of child abuse, major depressive disorder, borderline and antisocial
personality disorders, and posttraumatic stress disorder, among others (refer to text for more detail). Right panel: in situations of amygdala-
driven bottom-top communication, as is seen in anxiety disorders, posttraumatic stress disorder, and borderline personality disorder, portions
of the sgACC and the dACC may be preferentially activated and access the dlPFC, resulting in excessive cognitive control, attempts to suppress
distressing memories, and lack of attunement with one’s own emotional response, given the lack of inhibitory feedback onto the amygdala;
in (b), solid lines represent excitatory connections and dashed lines, inhibitory connections. dlPFC = dorsolateral prefrontal cortex; vmPFC
= ventromedial prefrontal cortex; OFC = orbitofrontal cortex; Am = amygdala; HC = hippocampus; Hy = hypothalamus; sg = subgenual
anterior cingulate cortex; ros = rostral anterior cingulate cortex; dACC = dorsal anterior cingulate cortex. The sgACC has connections to
both the vmPFC and the dlPFC, the implications of which are described in the text. This depiction is of the medial surface of the brain; the
dlPFC and portions of the OFC are located on the superolateral surface of the cerebrum, and their representations here are schematic.
The dorsal (“cognitive”) subdivision will include the 2.2.1. Implications for Early Life Adversity. As mentioned,
dorsal ACC (dACC), the hippocampus, the supplementary the right hemisphere is instrumental in the emotional
motor area (SMA), the parietal cortex, and the dorsolateral attunement between individuals, involved, for instance, in
PFC (dlPFC). As will be discussed, the sgACC also factors detecting facial cues in others [111]. The mother-child dyad,
into the dorsal subdivision, which is germane in certain psy- on a neurocircuitry level, activates multiple circuits involving
chiatric disorders. While the dlPFC is involved in executive positive/negative valence, empathic attunement, and reward.
functioning, temporal information processing, the overcom- When a mother looks at her child, areas activated include
ing of cognitive interference, and task switching, it may also the amygdala, OFC, and fusiform gyrus; the latter two areas
be involved in emotional avoidance and in the suppression have been described as forming the “neural signature” of the
of unwanted memories and in avoidant behaviors towards parental response to the child’s face, being activated on the
others [98]. Faulty activation may also lead to attributing order of milliseconds (implicating that there is a reward/risk
consideration that immediately happens when a mother
excessive salience to particular thoughts and stimuli/objects,
interacts with her child) [112–114]. The attuned mother will
leading to perseverative and ruminative thinking and a
interact in a manner which is experienced as rewarding for
difficulty in negotiating novelty. Thus, potentially emotional her and soothing for the child; indeed, appropriate release
stimuli (including interactions with others) may be handled of oxytocin enhances maternal neural plasticity [115, 116].
through strategies which deploy excessive cognitive control The rewarding nature of this interaction is illustrated by
[99], as opposed to the greater cortical-subcortical connectiv- mesolimbic dopamine release [117] and activation of the NAc
ity described with the ventral subdivision, leading to a lack of [118]. Cortically, the mother’s ability to attune to her child is
attunement with others and indeed with one’s own emotional dependent on activation of the mPFC which, as discussed, is
response. The dACC has a role in pain perception, response involved in the mentalization circuitry; this area is activated
selection, emotional regulation, and the fear response. It has when the child is showing signs of distress, indicating the
been implicated in a sense of social exclusion [100] and mother’s ability to understand its suffering and provide
has also been associated with child abuse and PTSD [101]. comfort [119]. Thus, the mPFC is key in an individual’s ability
In effect, there seems to be an inverse correlation between to access his or her own emotional response in a measured
vmPFC and dACC activity [102]. Preferential activation of manner, as well as allowing for access and understanding
the dACC can facilitate expression of the fear response, as of the emotional states of others. Lack of ability to do this
it directly projects onto the BLA, which in turn activates adequately can lead to feeling overwhelmed by affectively
the central amygdala (CeA), leading to brainstem nuclei charged situations, requiring cognitive evasion strategies.
stimulation and an autonomic response. Importantly, the This has relevance in the development and consolidation of a
vmPFC is bypassed in this process; the latter has a role child’s attachment schema, which begin to take shape within
in decreasing amygdala hyperactivity by projecting onto the first year of life. A misattuned mother may not be able to
GABAergic intercalated cells (ITC) in the amygdala, which empathically connect with her child, limiting her abilities to
will inhibit the CeA and dampen the autonomic response be soothing in moments of distress, and contributing to the
[102]. With increased activity of the dACC, the ability of child’s perception that such moments may not be amenable
an individual to empathize with others may be compro- to finding comfort in another person. Misattunement in
mised, and juvenile offenders with callous-unemotional traits itself predicts subsequent disorganized attachment in the
exhibit enhanced connectivity between the dACC and the child [120], speaking to this internalization and “organizing”
amygdala [103]. The dACC is a pivotal area in the social schema of how interpersonal relationships are negotiated
feedback network, integrating the dorsal and medial PFC moving forward. This can be noted when the mother looks
[104]; thus, the valence of particular interpersonal input may at her child and shows signs of shame, fear, disgust, or disso-
be more strongly negative depending on the dACC activity ciative phenomena, among others; this can have a profound
level. Of note, it has been suggested that this brain area would impact on the child initially on a sensorimotor, autonomic,
need to be activated in order to promote psychotherapeutic and affective level and eventually take on greater cognitive
change, particularly in modalities which would necessitate dimensions [121, 122]. Attachment schema have been shown
attunement and mentalization strategies [105]. One can speak to be transmitted transgenerationally [123, 124], and the
of a “lateral bias” in circuitry activation when the dorsal maternal neurocircuitry template deployed in interpersonal
subdivision is predominantly activated, something which is interactions can be passed down also. The establishment of
observed in multiple psychiatric disorders [106–110], as will such patterns of attachment early on is particularly relevant
be discussed in detail later. Many of the conditions in question given that early internalized representations have been shown
have symptom spectra in which faulty emotional processing to correlate with relational patterns displayed as an adult
and preferential (and many times maladaptive) activation [125]. Speaking more specifically to the neural circuitry acti-
of cortical pathways occur which inform consolidated and vated in mothers who themselves show insecure attachment
ruminative negative views of oneself and/or their environ- and are faced with their distressed child, what is noted is
ment. This circuitry illustrates the powerful influence that the predominant activation of the dorsal subdivision, in partic-
limbic structures can have on an individual’s default appraisal ular the dlPFC, suggesting attempts to use cognitive control
and behavioral responses and may perpetuate the template strategies to handle the situation [126]. She will also show
that certain situations cannot be thought about and processed decreased activation in the ventral striatum (where the NAc is
appropriately. located), indicating a lack of a hedonic response, and
Abused child
Insecure mother
FC FC
dlP dlP
pSTS
BG BG
vmP vmP
FC FC
OFC FG OFC
AI AI
Am Am
Preferential activation Preferential activation

Hypoactive area Hypoactive area
(a) (b)
Figure 2: Demonstration of the transgenerational transmission of a neurocircuitry template of misattunement. (a) demonstrates the pattern
observed in the insecure/misattuned mother. When looking at her child, a mother will quickly access a complex interconnected network,
including facial identification areas (FG) and empathic attunement areas (vmPFC and pSTS). Importantly, in addition to these areas,
there is connection with areas of the brain which are involved with immediately valenced reactions (amygdala), reward-risk considerations
(OFC), and feelings of empathy versus disgust and shame (insula). Thus, there is a prominent subcortical input which will inform whether
approaching one’s child is something considered desirable or potentially dangerous. The misattuned mother will preferentially activate
cognitive control areas (dlPFC) as opposed to the more empathically attuned vmPFC; in addition, there is heightened activation of the anterior
insula (associated with social pain and unfairness) and lessened activation of areas of the VS (associated with reward to external stimuli). Thus,
the model for avoidance of emotional attachment is engendered, and there is a corollary in this mother’s child, which is illustrated by the CNS
findings in the abused child. (b) illustrates the findings seen in a child who has suffered abuse, which seem to mirror in some important ways
what was seen in the mother. Hyperactivity of the amygdala and decreased volume of the hippocampus can result in highly affectively driven
responses to stimuli without access to contextual data which would allow for a less polarized reaction; thus, the greater input of the amygdala
will drive the OFC balance and favor the dlPFC with regard to how the environment is negotiated; hypoactivation of the vmPFC will impair
one’s ability to control this amygdala response and promote fear extinction. Also, the child shows a diminished ability to see the potential
positive value of rewarding stimuli due to hypoactivation of the corpus striatum, impacting how interpersonal interactions are seen, and
creating a model of mistrust and negativity when dealing with other people. FG = fusiform gyrus; vmPFC = ventromedial prefrontal cortex;
pSTS = posterior superior temporal sulcus; OFC = orbitofrontal cortex; dlPFC = dorsolateral prefrontal cortex; BG = basal ganglia; Am =
amygdala; AI = anterior insula; HC = hippocampus. As shown in the figure, green arrows indicate greater or preferential activation, whereas
orange arrows indicate the opposite. As mentioned in Figure 1, this depiction is of the medial surface of the brain; the dlPFC, portions of
the OFC, pSTS, AI, and FG are located on areas of the superolateral and inferior surfaces of the cerebrum, and their representations here are
schematic.
heightened activation of the anterior insula. The insula is a the mother, during crying episodes, activation of the amyg-
complex cortical area which is involved with anticipating and dala, parahippocampal gyrus, and insula; more specifically,
experiencing negative outcomes [106], as well as being inte- disorganized attachment behaviors will lead to the mother
grated into the empathic response network; its interoceptive decreasing activation of areas of the ventral subdivision,
integrative function allows for one to appreciate a “visceral” including temporal areas and the sgACC [127], furthering the
response to a stimulus, and hyperactivation may be involved challenge of attuning to a child, given the negative response
in a sense of disgust and social unfairness and pain. Thus, bias circuitry which becomes activated, perpetuating the
the interaction becomes one of displeasure which needs to be dyadic misattunement.
avoided, something with profoundly disorganizing effects on
the child. It should be noted that, given the essentially two- 2.2.2. Transgenerational Transmission of “Misattuned Tem-
person dynamic of dyadic attunement, the child’s response plate”. As mentioned, transmission of attachment schema
to the mother is also responsible for activating different from adult to child has been extensively shown in the
maternal circuits depending on the feedback she receives literature. Figure 2 illustrates several areas implicated in
from the child. Thus, it has been shown through a functional the maternal ability to respond to her child, and how this
magnetic resonance imaging (fMRI) study that children information is integrated into ventral and dorsal circuitry,
showing more insecure attachment behaviors will activate in which may cause a greater sense of connectedness or a feeling
of misattunement. The “internal working model” [128] the 3. Environmental Input and
child carries forth lends itself to a reenactment of what has Effects of Psychotherapy
been learned through his or her earliest interactions, on an
affective and behavioral level. Though questions have been This section will expand upon the genetic and circuitry
posited regarding the strength of the association [129, 130], concepts discussed thus far. Particularly, the ever-dynamic
abusive parenting and maternal insensitivity/misattunement interaction between the environment and the established
may be passed down from one generation to the next epigenetic and neural footprints will be discussed and how
[131]. In addition, abused children may grow up to display continued input can effect change throughout the course of
interpersonal violence in other settings (outside the parent- one’s life, for better or for worse, depending on how nurturing
child dyad), as both abusive and abused parties [132, 133]. The or challenging circumstances are. It is known that EE has
presence of a laterally biased neurocircuitry template (largely been associated with hippocampal neurogenesis, particularly
favoring networks within the dorsal subdivision detailed in the dentate gyrus [150, 151]; there is also a demonstrable
earlier) has also been demonstrated in studies of individuals effect of EE on synaptogenesis and dendritic branching [152].
suffering abuse as a child, showing parallels with the circuitry In keeping with the concept of the importance of continued
discussed above for the misattuned mother. Child abuse environmental input in the face of plastic changes, it should
has been associated with heightened responsiveness of the be noted that new hippocampal neurons require at least a
amygdala (including for neutral stimuli) and of the insula two-week period to mature before being able to contribute
[134–136]. This shows the maladaptive template of sensed to cognitive functioning [153], underlining the susceptibility
environmental danger and self-identification as an unworthy during this period and the need to take the notion of neuro-
and shameful individual. There is also a hypoactivation of genesis cum grano salis. This is why facilitating gene plasticity
areas within the ventral cortical system, thus limiting the abil- (e.g., BDNF gene) through demethylation or creating new
ity to control one’s hyperarousal. Decreased activity in abused neurons is not an inexorably positive change, and this is
children has been shown in areas of the temporal lobes, where the concept of “differential susceptibility” becomes key,
hippocampus, the mPFC, the OFC, and the ventral ACC as will be discussed.
(vACC) [134, 137, 138]. The vACC hypoactivation gives way
to preferential activity within the dACC [139]; thus, the child’s 3.1. Gene Plasticity and Epigenetic Influence. DNA methy-
own emotional awareness and the ability to express his or lation, histone acetylation, and the presence of noncoding
her feelings may be impaired. In addition, abused children RNAs are implicated in memory formation [153] and are the
show a decrease in their ability to anticipate and process target of current research to understand the influence of EE
environmental cues experienced as rewarding, as demon- on epigenetic markers, with consequent impact on cognitive
strated by hypoactivation of the corpus striatum [140, 141], processes [154]. Environmental stimuli can lead to neuronal
impairing dopaminergically driven hedonic responsiveness. plasticity by dynamically inducing chromatin modifications
This underlines how interpersonal reactions are experienced [155].
as unrewarding and potentially dangerous. Corollaries can As mentioned earlier, VTA-NAc BDNF release can have
be found in animal models; for instance, maternal separation a prodepressant effect in chronic stress. A study by Wook
in rodents can lead to decreased sensitivity to opioids [142]; Koo et al., employing a 10-day chronic social defeat stress
also, chronic social defeat can lead to a decrease in affinity (CSDS) protocol in mice, showed that BDNF signaling in
for natural rewards (e.g., sucrose solution), which is a model the NAc is the primary mediator of CSDS-induced social
for anhedonia and can develop conditioned place preference avoidance (as opposed to dopamine) [156]. This was sup-
(CPP) for low doses of cocaine (insufficient to produce CPP in ported by demonstrating an exacerbation of social avoidance
controls), showing a preference for more strongly reinforcing via phasic optogenetic stimulation of the VTA after the
substances to achieve a hedonic response [143]; these two defeat episodes. In addition, intra-NAc infusion of a BDNF
examples may have translational relevance regarding the tyrosine receptor kinase B (TrkB) inhibitor blocked the social
cooccurrence of psychiatric disorders with substance use. avoidance induced by CSDS [156], as does local BDNF gene
Figure 2 outlines the transgenerational neural template of knockdown in the VTA [156, 157]. The relevance of this
abusive or misattuned parent-child dyads. function factors into a model of resilience to social stress.
Resilience itself is an active process [158], and individuals
demonstrating greater tolerance to adverse environmental
2.2.3. Lateral Circuitry Bias in Psychopathology. Establish- stimuli have shown adaptive gene expression which quanti-
ment of an early neural circuitry favoring the cognitive/dorsal tatively can surpass the expression of the more susceptible
subdivision (with particular emphasis on the dlPFC), in lieu organisms. A study by Krishnan et al. demonstrated that mice
of the affective/ventral one, has been shown to carry over which were susceptible to a social defeat model of depression
into later life and may inform subsequent psychopathology, showed much less of a genetic modulation as compared to
as there are similar patterns seen in a number of major the resilient group (the latter showing greater time spent in
psychiatric illnesses (e.g., anxiety disorders, MDD, PTSD, and an interaction zone with a social target, as well as increased
borderline and antisocial personality disorders). In Section 4, sucrose preference, despite being exposed to the same social
the pertinent neurobiology relating to these disorders will be defeat paradigm). More specifically, the resilient mice showed
reviewed, as will the effects of psychotherapy on these increased gene expression with an upregulation of the num-
circuits. ber of membrane potassium channels in the presynaptic
neurons projecting from the VTA to the NAc, with a dimin- models [164, 165]. Chronically stressed mice were given long-
ished release of BDNF, results which suggest a decrease in term treatment with fluoxetine and then exposed to either
the synaptic consolidation of the adverse response to the EE or a continued stressful environment. In the EE group,
defeat model [143]. This defeat model exemplifies a level of there was a decrease in depression-like behaviors, an increase
continued negotiation of the environment in a more adaptive in hippocampal BDNF, and a decrease in corticosterone. In
way, as opposed to adopting a passive response and avoidance the adverse environment group, despite being on fluoxetine,
after social defeat, a difference which may carry evolutionary there was a worsening in the depressive symptoms, lower
implications. BDNF levels in the hippocampus, and higher corticosterone
The impact of the environment cannot be viewed only levels as compared with before fluoxetine was introduced.
through the lens of the resilience-susceptibility dichotomy. Thus, as has been suggested before [166], it is more important
This has been shown in animal models in which the exper- to consider genes as plastic as opposed to seeing them
imental group has been specifically bred to demonstrate a in a dichotomous manner. The human corollaries may be
depressive phenotype. The study by Mehta-Raghavan used expanded upon through further research. The STAR∗ D Trial
the Wistar Kyoto strain of rats and bred them to display sus- (Sequenced Treatment Alternatives to Relieve Depression)
ceptibility genes implicating 14 transcriptomic markers which indicated that there are environmental factors which con-
have been associated with MDD in humans; these genes tributed to a positive response to citalopram in humans
are involved in such processes as neurodegeneration, synap- (namely, income and employment status) [167]. Children
togenesis, neuronal migration, and hippocampal excitability and adolescents who have experienced early environmental
[159]. The susceptible and control group (termed “more disruption show a poorer response to fluoxetine, while those
immobile”: WMI, and “less immobile”: WLI, respectively, with greater measures of family functioning have shown
depending on how they performed in the forced swim greater rates of response [168]. An interesting parallel can be
test) were then either submitted to no intervention, chronic seen with D-cycloserine (DCS), an NMDA agonist which can
restraint stress (CRS), or to EE. With regard to EE, the WMI be used as an augmentation strategy for cognitive-behavioral
group showed improvement on the FST, and subsequent as well as exposure therapy for anxiety and trauma- and
mobility levels did not statistically separate from the WLI stressor-related disorders [169]. DCS can increase NMDA
that had no active intervention. This indicates the potentially plasticity and accelerate responses to treatment; however,
corrective environmental impact despite prominent genetic this can facilitate extinction or enhance consolidation of fear
susceptibility. memories, depending on the success of the treatment [170,
The translational value of animal models is intriguing and 171]; thus, the patient can clinically worsen as a result of this
will require further elucidation with regard to its applicability adjunct in suboptimal treatment settings.
in humans. However, it seems incontestable that one’s genetic This notion of genetic plasticity is at the core of dif-
ferential susceptibility. To highlight this, two of the studies
make-up is not entirely deterministic, and the individual’s
mentioned above will be discussed, both by Caspi et al. [15,
environment will continue to shape gene expression over
16]. In the study investigating the role of hypofunctioning
time. This paper posits that psychotherapy serves as a positive
MAO-A alleles, the negative outcomes (antisocial personality
environmental input (something akin to EE). The split model disorder, conduct disorder, conviction for violent offenses,
of psychotherapy and medication management, something and disposition toward violence) only occurred in the event
which is becoming more mainstream within psychiatric prac- of early life adversity [15]. When looking at the group that
tice, indicates that there is a structural dissociation within the did not suffer maltreatment, the studied outcomes pertaining
treatment model which may not be grounded on where the to the spectrum of antisocial behavior and personality traits
evidence base is leading. Many patients end up only choosing were actually found to be less than the group with the nor-
to take medications and not engage in therapy. Even those mally functioning alleles. Thus, the excess of neurotransmit-
who do psychotherapy (which may be limited to very few and ters conferred by the hypoactive MAO-A proved to be more
irregular encounters) may be immersed in an environment adaptive in optimal settings. While an excess of monoamines
outside the treatment setting which may be quite detrimental can be associated with psychopathology, increased levels
and much more impactful than the work the therapist is of noradrenaline and dopamine can also be associated,
trying to carry out. As mentioned, even with newly generated given the proper environment, with prosocial and egalitarian
neurons, there is a “labile period” during which the continued behaviors, as well as with cognitive flexibility [172, 173], all of
input of the environment will inform whether or not adaptive which are diametrically opposed to typical antisocial traits.
or maladaptive memory reconsolidation will occur; in the A similar phenomenon has been described with regard to
case of the latter, already existing dysfunctional behavior may predisposition to ADHD and MAO-A levels [174]. In a similar
be exacerbated [160]. It is known that antidepressants can vein, individuals homozygous for the 5-HTTLPR s allele
lead to BDNF demethylation, thus allowing for greater gene have shown more adaptive measures of social and mental
expression and hippocampal plasticity [161–163]. However, health functioning under nurturing conditions, as compared
the notion that medications can promote “gene plasticity” with individuals with the l allele. Serotonin, as mentioned,
(i.e., greater responsiveness to the environment, be it positive is involved with encoding of fear/threat processing; under
or negative), as opposed to unidirectionally leading to adap- optimal conditions, this neurotransmitter will perform this
tive changes, needs to be considered in light of the split model. function in tandem with GABA and allow for adaptive
Two studies in particular have highlighted this in rodent responses to the environment without an excessive arousal
of the fear network [22]. This is applicable to depressive The dopamine receptor 4 (DRD4) is part of the D2-like
symptoms [175, 176], anxiety [176], and ADHD [20]. Thus, family of dopamine receptors and contains seven transmem-
how neurotransmitters are deployed will be contingent on brane domains; it has been shown to be present in the meso-
more permissive or limiting environmental factors. An exam- corticolimbic pathway, being thus implicated in cue reactivity
ple of this would be that individuals with anxiety disorders and in the reward pathway [197]. The DRD4 variable number
homozygous for the s allele may be more responsive to of tandem repeats (VNTR) polymorphism (exon 3) has also
cognitive-behavioral therapy (CBT) [177], showing a greater been a subject of attention with regard to GxE interactions as
ability to benefit from the environmental modifier offered; they pertain to the reward system. This VNTR is suggested
however, this finding has been challenged by some authors to be implicated in downstream changes in cyclic adenosine
[178, 179]. monophosphate (cAMP) expression [198]; more specifically,
Though no studies as to the knowledge of this author the long (L) allele is associated with a decrease in ligand
have been conducted looking at the effects of psychotherapy binding and reduced cAMP formation when dopamine binds
in interaction with genes implicated in anticipation and to the receptor [198, 199]. The L allele is thus associated with
processing of rewarding stimuli, they may be a target for a decrease in mesocorticolimbic dopaminergic transmission,
future research. As mentioned earlier, early life adversity can resulting in increased craving and arousal to cues relating to
be associated with decrease in reward sensitivity; however, potential rewards [197, 200]. These individuals have shown,
distinct patterns have been described with respect to the two when raised in conditions of socioeconomic disadvantage, to
stages (i.e., anticipating and processing rewards). Functional prefer smaller immediate rewards over those that are larger
imaging studies have shown a decrease in basal ganglia and more delayed, highlighting the interaction with adverse
(BG) and ventral striatum (VS) responses during reward environmental influences as it relates to reward sensitivity;
anticipation [141, 180], but a greater response in these areas the differential susceptibility factor has been highlighted by
during delivery of the reward [181]. Within the spectrum the greater appreciation of future rewards of people with this
of psychopathology, control individuals with impulsive traits polymorphism in the absence of adversity [201].
[182], as well as individuals with psychiatric diagnoses pre-
disposing them to impulsive actions, such as ADHD, have 3.2. Epigenetic Changes Observed with Psychotherapy. Given
shown heightened reward sensitivity and VS response to the established importance of continued environmental input
incentives [183, 184]. Studies have aimed to understand the on epigenetic modifications, research has begun to emerge on
effects of adversity on individuals with particular gene varia- such changes as they relate to the effects of psychotherapeutic
tions. The catechol-O-methyl transferase (COMT) enzyme is interventions. Some of the genes discussed previously in this
involved in the breakdown of catecholamines. The Val158Met paper have been the target of these research efforts, and
polymorphism is characterized by a replacement of valine these studies will be reviewed in more detail. Importantly,
by methionine at codon 158 on chromosome 22q11.21. Indi- while some forms of psychotherapy will be mentioned in
viduals homozygous for the Met allele display a decrease this section, they will be elaborated on in greater detail in
in COMT function, with resultant higher synaptic PFC Section 4.
dopamine levels [185, 186]. This can result in limited flexibility Methylation of the BDNF gene has been associated with
in processing rewarding stimuli. Indeed, Met homozygotes BPD [202], particularly given this disorder’s high rate of
have been shown to display increased activation of the childhood abuse. Dialectical behavioral therapy (DBT) has
PFC and VS when anticipating rewards [187, 188] (though a strong evidence base for treating this condition, and the
another study only found increased PFC activation) [189]. effects of DBT on BDNF gene methylation have been assessed
In instances of stress during childhood, Met homozygotes (DBT will be described in greater detail later) [51]. In this
displayed ACC and VS hyperactivity at reward delivery, study, 115 patients were assessed after four weeks of DBT.
highlighting the gene versus environment (GxE) implications Nonresponders showed an increase in methylation of the
of this polymorphism [190, 191]. Given the heightened reward BDNF gene exons I and IV (as assessed by bisulfite treatment;
responsiveness, studies have extended to investigate whether DNA was extracted from leukocytes), while responders
the association ties into psychopathology; despite no clear showed a decrease in methylation; these results held when
association emerging between COMT and illicit substance adjusted for medication effects (all patients in the study were
use per se (with the possible exception of tobacco use disor- medicated concurrently). Decreases in methylation corre-
der) [192], increased VS activation for Met carriers parallels lated with symptomatic improvement (depressive symptoms,
the activation noted in the VS in substance users compared hopelessness, and impulsivity); on the depression scale, only
to controls when positive incentives were provided [193]. those with greater than 70% improvement (as assessed by
Expression of this allele, in combination with childhood the Beck Depression Inventory II) showed a statistically
adversity, may lead to a heightened pleasurable experience significant decrease in methylation.
when under the influence of substances, potentially increas- Prolonged exposure (PE) is an intensive structured psy-
ing the risk of subsequent use disorders [190, 191, 194]. chotherapy utilized for PTSD [203] (refer to description later
Curiously, there is a decrease in reward anticipation and in this paper). One study looked at the predictive value of GR
increase in reward responsiveness in adolescents, with the NR3C1 (exon 1F) and FKBP5 methylation on the response to
effects of the polymorphism showing a parallel with this 12 weeks of PE in patients with PTSD [204], as well as the
population (which seems to have more hedonically drive and response-methylation correlation after treatment (peripheral
consummatory behaviors) [195, 196]. mononuclear cells were utilized). Higher pretreatment levels
of GR methylation were associated with greater response nonresponders (decrease). The parallel traced is between a
to PE. In contrast, there was no clear predictive value of higher SERT DNA methylation (which replicates the s allele
pretreatment FKBP5 methylation on response outcomes. of the 5-HTTLPR) and greater responsiveness to treatment;
Treatment responders showed a negative correlation between the lower the expression of the gene, the greater the individual
GR 1F methylation and self-reported PTSD symptoms. would be able to respond to the positive environmental
Conversely, they displayed a correlation between decreased input, and the epigenetic modifications seen with successful
FKBP5 methylation and lower scores on the Clinician- treatment would seem to facilitate this potential for continued
Assisted PTSD Scale (CAPS) after treatment. Both of these improvement.
epigenetic changes correlated with an elevation in cortisol Controversy remains about the value of measuring
levels posttreatment. It has been demonstrated that clinical methylation changes in specific genes as an indicator of
response to brief eclectic psychotherapy in patients with treatment response; it has been questioned what the value
PTSD can lead to an increase in cortisol levels [205], show- is of assessing methylation in peripheral tissue. It has
ing a neuroendocrine parallel with the epigenetic changes been challenging to demonstrate direct correlations between
outlined. While improvement in symptomatology may be peripheral blood cell and brain methylation [208, 209].
associated with a decrease in cortisol reactivity [206] (high However, MAO-A gene methylation in leukocytes has been
reactive levels being associated with consolidation of trau- shown to be inversely correlated with MAO-A levels in the
matic memories) [207], higher baseline levels of cortisol may brain [208, 215], highlighting the utility of this measurement.
be more adaptive in PTSD given the mitigating effect of Also, authors have argued that, with regard to buccal tissue,
cortisol on release of norepinephrine (NE) from the locus the lower cell heterogeneity and a degree of developmental
coeruleus. commonality with brain tissue would make it a promising
In a study employing CBT to treat panic disorder, MAO-A option for methylation studies [216]. This burgeoning field
gene methylation was analyzed (in blood cells) with regard to will hopefully continue to yield elucidating data.
treatment response [208]. Panic disorder has been associated
with hypomethylation (hence greater expression) of this gene
[209], with an inverse correlation found between methylation 4. Changing Default Neural
and symptom severity [208]. In the Ziegler et al. study [208], Circuitry Activation
after six weeks of therapy, responders were shown to have
increased methylation of the MAO-A gene (reaching levels One change that can be fostered by psychotherapy is modi-
similar to controls), while nonresponders showed further fication of default activation patterns involving the circuitry
demethylation. From a neurobiological standpoint, the excess described before. Resting-state functional connectivity and
of serotonin which would result from increased methylation task-related functional imaging have increased understand-
of MAO-A would serve to decrease the activation of areas ing of how particular areas of the brain can maintain
of the brain involved in the avoidance and fear responses, as maladaptive modes of thinking and behaving, as well as the
well as in the heightened autonomic response characteristic implications of medication and psychotherapeutic treatment
of panic attacks, such as the dorsal PAG [210]; this would strategies in reconfiguring connectivity in tandem with clin-
allow for more rostral areas (e.g., PFC, septum-hippocampus, ical improvement or lack thereof. Dorsal or ventral bias can
and amygdala) to be activated and facilitate a more adaptive inform more or less functional connectivity with subcortical
response [211]. areas and also underlie the degree of flexibility that can be
Expanding the discussion surrounding SERT and epige- elicited when interacting with particular stimuli. Though the
netic modifications, a study was conducted to assess how CBT dlPFC may be anomalously and excessively activated in mal-
would affect transporter methylation in children with anxiety adaptive cognitive appraisal, it is, along with the hippocam-
disorders (buccal swabs were performed for DNA collection) pus, also one of the key areas of the brain that will need to be
[212]. SERT methylation has been associated with adverse life accessed to allow for psychotherapy to be effective [217], given
events, including child abuse [213, 214] and, as mentioned, that the content of one’s ruminations and fixations need
expression of this transporter (with its consequent impact on to be allowed room for exploration in order to promote
serotonin availability) can impact how responsive an individ- flexibility and for an understanding of one’s preoccupations
ual will be to psychological treatments [177]. Most patients in to be processed and worked through. This would potentially
the Roberts et al. study were diagnosed with generalized anxi- allow for a greater fluidity between emotional appraisal and
ety disorder (GAD); responders showed a nonstatistically sig- regulation, the latter implicating ventral structures (including
nificant increase in SERT methylation, while nonresponders the vmPFC), which in itself allows for a more measured
showed a significant decrease in methylation (𝑝 = 0.037). control of subcortical activation [99, 218]. The vmPFC is
Interestingly, the authors conducted a follow-up assessment paramount in the therapeutic response, given evidence that
six months after the treatment was completed, and there only engaging dlPFC and other lateral PFC regions may
was a significant increase in methylation for participants that not be sufficient to mitigate amygdala reactivity to negative
continued to show symptom improvement during this time stimuli [219]. The hippocampus will allow for contextual
period (an indicator of consolidated learning) as compared consolidation of the response to treatment. Importantly,
to those that showed no improvement or worsened (𝑝 = certain activation patterns, though involved in particular
0.003). Thus, at follow-up, there was a significant difference symptom spectra, may also be prognostic indicators of a
in SERT methylation between responders (increase) and positive response to treatment, as engaging these areas while
working therapeutically may help to reconfigure their role show increased or decreased activation, depending on the
within the neural circuit. For instance, ability to engage function which is being assessed. With the ruminative and
the hippocampus, which gauges the potential to provide poor self-view aspects, as well as the negativity bias toward
greater contextual input to counter generalizations in belief external stimuli, there is an increase in dlPFC activity [108,
and response patterns, has been shown to predict treatment 241, 243, 244]. This is compounded by the concurrent vmPFC
response to CBT in adults with panic disorder (PD) and hypoactivation [109, 241], which contributes to difficulty
GAD [220]. The neuroimaging literature of psychotherapy with reappraisal of negative thoughts. However, the dlPFC
will be reviewed in this section, focusing mainly on the effects is underrecruited when the tasks involve frame shifting and
of psychotherapy on conditions in which bias favoring the inhibition, executive control, and planning [222, 245, 246].
dorsal system is well established (anxiety disorders, MDD, There may also be differences between right and left dlPFC
PTSD, and BPD). A brief review of neurobiology will be activation in MDD depending on the affective valence of
provided prior to describing the effects of different forms of decision-making processes [247]. Decrease in frontostri-
psychotherapy. Tables 1–3 provide a synthesis of the studies atal responsiveness to reward has been described; this
outlined. includes decreased anticipation and enjoyment of rewarding
objects/stimuli, as well as a bias towards overestimating
4.1. Neurobiology of Conditions with Lateral/Dorsal Bias failure [248–250]. In MDD, there is also difficulty in main-
taining activation in the NAc during attempts to consciously
4.1.1. Anxiety Disorders. In the setting of anxiety, there is upregulate positive emotions [251].
a bias in an individual’s interpretation of the environment
[107, 221], with a heightened perception of threat, a decreased 4.1.3. Posttraumatic Stress Disorder. In PTSD, one of the
recruitment of the PFC during emotionally regulated tasks most described neurobiological findings is a decrease in the
[222], and an increase in amygdala and anterior insula volume of the hippocampus [252]. There is an increase in
responsiveness. Consequently, there is a difficulty in the gen- activity in the amygdala (leading to kindled fear acquisition
eration of different outlooks on a given situation [223], thus networks) and in the insula [253], as well as an increase
the maladaptive response feeds into itself, and the “bottom- in hippocampal activity when encoding negatively valenced
up” response is maintained [224]. Altered patterns of func- stimuli [254]. Sensitization of the dACC is associated with an
tional connectivity occur in corticocortical and cortical- increase in the appraisal of threat and expression of fear and
subcortical networks (e.g., increased amygdala-dACC and correlates with the heightened activation of the insula and
decreased mPFC-OFC connectivity) [211, 225, 226], in tan- amygdala [101, 255]. Difficulty with modifying this response
dem with preferred activation of cortical areas favoring rumi- pattern derives from hypoactivation of the rACC, vmPFC and
nation, negative affective cognitions, and decreased cognitive of the hippocampus during fear extinction [255].
appraisal (e.g., dlPFC and inferior frontal gyrus (IFG)) [218,
227–230]. As a result, the anxious individual has an atten-
tional bias and difficulty disengaging from threatening stim- 4.1.4. Borderline Personality Disorder. Cluster B personal-
uli, magnifying the cognitive inflexibility and leading to over- ity disorders, in particular BPD and antisocial personality
generalization [228]. This is seen pervasively in GAD, which disorder (ASPD), are associated with heightened affective
is associated with persistent anxiety symptoms, leading to responses to the environment with behavioral overswings
autonomic arousal and diffuse preoccupations and ruminat- without PFC modulation; it is important to highlight that,
ing about numerous situations in an individual’s life, without in the case of ASPD, this applies to cases more commonly
necessarily being attached to circumscribed cues, as in pho- associated with child abuse and in which violence is reactive
bias. Excessive attention to social cues and rumination about as opposed to proactive, the latter being associated with psy-
environmental stimuli, as seen in social anxiety disorder chopathic traits, and thus with different patterns of emotional
(SAD), have also been associated with increased connectivity reactivity and autonomic arousal [256, 257]. Both of these
between the amygdala and more dorsal areas of the PFC, personality disorders have been associated with heightened
with a concurrent decrease in amygdala-vmPFC connectivity amygdala reactivity, as well as a decrease in vmPFC, reflecting
[231, 232]. As stimuli become more proximal, activation of the difficulty in identifying emotional states in others that are
fear-system components will move from lateral to central not inflexibly perceived as menacing [257–259]. Also, in BPD
amygdala, with subsequent activation of PAG and brainstem there is enhanced connectivity between the dACC and the
nuclei, inducing a more pronounced panic response [233]. Of amygdala and insula, heightening focus on social cues with
note, phobic disorders and PD are variably associated with individually ascribed salience [260].
increased activity in the CeA, insula, and PAG [234–236]. In the following section, different forms of psychotherapy
and their effects on the described circuits will be described in
greater detail.
4.1.2. Major Depressive Disorder. MDD has been associated
with greater activity in areas of the brain associated with the
processing of emotionally salient stimuli, including the amyg- 4.2. Psychotherapeutic Modalities and
dala and sgACC [237–240]. The amygdala may also lose its Effects on Neurocircuitry
ability to discriminate between neutral and emotional stimuli
[241]. Decreased volumes in the hippocampus, BG, and in 4.2.1. Cognitive-Behavioral Therapy (CBT). CBT is a typically
the OFC have also been demonstrated [242]. The dlPFC can time-limited form of treatment which involves cognitive
Table 1
(a) Description of psychotherapy and neuroimaging studies: CBT for anxiety disorders∗ .
Number of
patients
Diagnosis Study Design Treatment effects of psychotherapy
(intervention
group)
Normalization of hyperactivation in IFG.
Greater connectivity between IFG and:
Kircher et al. 42 fMRI amygdala, hippocampus, ACC, mPFC, and
(2013) (unmedicated) 12 weeks of CBT lPFC
Decrease in activation in the amygdala,
anterior insula, dACC, rACC, and vmPFC
Normalized hyperactivation of pgACC and
PD fMRI amygdala. Increase in hippocampal
Lueken et al. 49
12 sessions of CBT (twice-weekly for six activation with stimulus contingency
(2013) (unmedicated)
weeks) processing
Enhanced ACC-amygdala coupling
fMRI In therapist-guided group, there was an
Straube et al.
42 12 sessions of manualized CBT increase in activation of the hippocampus,
(2014)
(unmedicated) Patient-guided and therapist-guided as well as a decreased connectivity between
[144]
protocols were compared left IFG and left hippocampus
CBT group: decrease in limbic, paralimbic,
and PAG hyperactivation. Results
maintained at one-year follow-up (multiple
PET scan
brain areas needed to be included to reach
Furmark et al. 18 CBT for eight weeks (each session was 3
SoP statistical significance).
(2002) (unmedicated) hours)
Citalopram group: decrease in thalamic
Compared with citalopram-only group
hyperactivation (suggesting decreased
sensory input into the amygdala); decrease
in vPFC activation
Paquette et al. 12 fMRI Decrease in activation in dlPFC and
(2003) (unmedicated) 4 sessions parahippocampal gyrus
Anticipation: decreased cerebral blood flow
fMRI (CBF) in bilateral parahippocampal gyri,
SP Soravia et al. Unspecified number of CBT sessions ventral anterior thalamus, Brodmann area 8,
8 (unmedicated)
(2016) (though scanning done one month after and the ACC
treatment started) Postprocessing phase: reduced CBF in the
bilateral insula and motor cortex.
Straube et al. 28 (unclear if fMRI
Decrease in activation in ACC and insula
(2006) medicated) 2 sessions (4-5 hours each)
fMRI
Maslowsky et al. 8 weeks of CBT Increase in activation in vlPFC to angry
7 (unmedicated)
(2010) Comparison group was patients on faces
fluoxetine
12
(unmedicated)
McClure et al. fMRI Decrease in amygdala activity (not
(3 with a
(2007) 8 weeks of CBT statistically significant)
diagnosis of
social phobia)
GAD
Before treatment, patients showed blunted
responses to positive faces in the amygdala,
insula, and ACC; they also showed
heightened amygdala-insula and
Fonzo et al. 21 fMRI amygdala-precuneus connectivity
(2014) (unmedicated) 10 sessions of CBT After treatment: decrease in activation to
angry and fearful tasks in the sgACC and
amygdala.
Increase in activation to happy tasks in the
anterior and posterior insula
(a) Continued.
Number of
patients
(intervention
group)
Activation changes in areas of lPFC, vPFC,
Doehrmann et 39 fMRI
and in the amygdala, none statistically
al. (2013) (unmedicated) 12 weeks of CBT
significant
Cognitive reappraisal of negative self-beliefs
was parameter assessed. Amygdala reactivity
Goldin et al. 75 fMRI
to negative self-beliefs remained consistent
(2013) (unmedicated) 16 sessions of CBT
over time
Increase in the dmPFC and dlPFC
Increase in the superior frontal gyrus,
middle occipital lobe, and inferior parietal
SAD
lobule activity when reacting to social praise
Goldin et al. 59 fMRI
Increases in right superior frontal gyrus and
(2014) (unmedicated) 16 weeks of CBT
inferior parietal lobule, and decreases in left
posterior superior temporal gyrus when
reacting to social criticism
14 (2 on
No significant correlation between symptom
Klumpp et al. bupropion, the fMRI
improvement and activation patterns in
(2013) rest 12 weeks of CBT
dmPFC or mPFC
unmedicated)
Yuan et al. 15 (4 on stable fMRI Attenuation of dACC-amygdala and
(2016) doses of SSRIs) 8 weeks of group CBT dmPFC-amygdala connectivity
∗
The following legend serves as a guide for all the tables in this paper.
d = dorsal; dl = dorsolateral; dm = dorsomedial; l = lateral; m = medial; pg = pregenual; r = rostral; sg = subgenual; v = ventral; vl = ventrolateral; vm =
ventromedial.
ACC = anterior cingulate cortex; AG = agoraphobia; BATD = behavioral activation treatment for depression; BDI = Beck Depression Inventory; BG = basal
ganglia; CAPS = clinician-administered PTSD scale; CBT = cognitive-behavioral therapy; DBT = dialectical behavioral therapy; EMDR = eye movement
desensitization and reprocessing; fMRI = functional magnetic resonance imaging; GAD = generalized anxiety disorder; IFG = inferior frontal gyrus; MDD =
major depressive disorder; OFC = orbitofrontal cortex; PAG = periaqueductal gray; PCC = posterior cingulate cortex; PD = panic disorder; PET = positron-
emission tomography; PFC = prefrontal cortex; PTSD = posttraumatic stress disorder; rCBF = resting cerebral blood flow; SAD = social anxiety disorder;
SERT = serotonin transporter; SoP = social phobia; SP = specific phobia; SPECT = single-photon emission computed tomography; SSRIs = selective serotonin
reuptake inhibitors.
(b) Description of psychotherapy and neuroimaging studies: CBT for major depressive disorder.
Number of
patients
(intervention
group)
SPECT
Amsterdam et 20 Increase in standardized uptake ratio in the midbrain
12 weeks of CBT (twice weekly
al. (2013) (unmedicated) and bilaterally in the medial temporal lobes
for four weeks, then weekly)
Less amygdala hyperactivity when exposed to sad faces.
16 fMRI
Fu et al. (2008) Normalization of amygdala-hippocampus activation
(unmedicated) 16 sessions of CBT
pattern
17 PET Increased activity in dACC, hippocampus, and
Goldapple et al. (unmedicated; 15–20 sessions of CBT parahippocampal gyrus activity
MDD (2004) 14 completed Comparison group was on Decreased frontal cortical activity mainly in the dlPFC
protocol) paroxetine and OFC
PET
16 weeks of CBT (at least 8 weeks
Decrease in metabolism bilaterally in the PCC
of treatment completed prior to
Kennedy et al. 12 (opposite to venlafaxine group), OFC, and in the left
rescanning; all but one patient
(2007) (unmedicated) dmPFC. Increase in metabolism in the right inferior
completed 16 weeks)
occipital cortex, in the sgACC, and in the vmPFC
Comparison group treated with
venlafaxine
(b) Continued.
Number of
patients
(intervention
group)
10 (1 medicated, fMRI
Klein et al. stable dose of 12 weeks of CBASP∗ (mean
(2014) venlafaxine for number of sessions was 15.8; each
months) session was 50 minutes)
15
(unmedicated) fMRI
Ritchey et al.
Data from 11 Weekly CBT sessions (average of Increase in vmPFC activity
(2011)
patients was 20.7 sessions and 30.3 weeks)
used
Decreased parahippocampal activity
Sankar et al. 16 fMRI
Increased activity in hippocampus, precentral gyrus,
(2015) (unmedicated) 16 weeks of CBT
inferior parietal lobe, and precuneus
Straub et al. 18 fMRI Decrease in bilateral amygdala, hippocampus, and
(2015) (unmedicated) 5 sessions of group CBT sgACC activity
23 (all on stable
doses of Activity during self-referential processing in vACC and
Yoshimura et al. fMRI
antidepressants mPFC was increased for positive stimuli and decreased
(2014) 12 weekly sessions of group CBT
for at least 8 for negative stimuli
weeks)
29 (all on stable
doses of fMRI
Yoshimura et al. Decrease in dysfunctional mPFC-ACC connectivity
antidepressants 12 weekly (90-minute) CBT
(2017) correlated with improvement on BDI score
for at least 8 sessions
weeks)
∗
CBASP = cognitive behavioral analysis system of psychotherapy.
(c) Description of psychotherapy and neuroimaging studies: CBT for posttraumatic stress disorder.
Number of
patients
(intervention
group)
14
(7 considered
fMRI After treatment, the CAPS score was
Bryant et al. treatment
8 weeks of CBT (including imagined and in positively correlated with amygdala and
(2008) responders, 3 of
vivo exposure) ACC activity
which were on
PTSD psychotropics)
29
(some on stable
Thomaes et al. fMRI Decrease in activation in anterior insula and
doses of SSRIs
(2012) 20 weekly sessions (group CBT) dACC to emotional Stroop
or benzodi-
azepines)
distortion analysis (including overgeneralizing and catas- and 1(c) detail the neuroimaging studies assessing neural
trophic thinking), situational reappraisal, exposure hierarchy markers of treatment response.
analysis, and several exposure components. It has a strong
evidence base for numerous psychiatric conditions, including (1) CBT for Anxiety Disorders. CBT can address both the more
various anxiety disorders as well as MDD [261]. Tasks utilized ruminative/cognitive-based symptoms of anxiety disorders
to assess efficacy of CBT attempt to replicate stimuli within an (as generated by diminished activation in medial PFC and
individual’s life which may elicit more generalized or specific areas of the ACC, with ineffective control of amygdala
fear-based responses. It is at the core of CBT to attempt a responses) as well as the more proximal fear-based responses
reworking of cognitive schema, accessing more flexible cor- (as outlined for phobias and panic disorder). Several studies
tical areas which may allay conditioned responses through have aimed at assessing the PFC-amygdala activation patterns
inhibitory connections to subcortical areas. Tables 1(a), 1(b), in response to treatment; this has been done through subject
Table 2: Description of psychotherapy and neuroimaging studies: miscellaneous psychotherapies.
Number of patients
Psychiatry Journal
Modality of psychotherapy Diagnosis Study (intervention Design Treatment effects of psychotherapy

group)
MRI
Bossini et al. (2011) 9 (unmedicated) 12 weeks (weekly Bilateral volume increase in the hippocampus
Eye movement
90-minute sessions)
desensitization and PTSD
SPECT Decreased tracer uptake in medial temporal cortex
reprocessing (EMDR)
Pagani et al. (2007) 15 (unmedicated) 8 weeks (five 90-minute (uncus), hippocampus, occipitotemporal cortex, and
sessions) visual cortex (BA 17)
fMRI
8
Felmingham et al. 8 weeks of treatment Increase in rACC activity and a decrease in bilateral
(2 on SSRIs; the
(2007) (cognitive restructuring amygdala activity
Prolonged exposure (PE) PTSD rest unmedicated)
with imaginal exposure)
Helpman et al. 16 fMRI Decrease in rACC activation and increased activity in
(2016) (unmedicated) 10-week PE protocol the mPFC
Brief eclectic Lindauer et al. 20 SPECT Decrease in rCBF in the right uncus
PTSD
psychotherapy (BEP) (2008) (unmedicated) 16 weekly sessions Increase in rCBF in the left superior temporal gyrus
fMRI Increase in regional homogeneity in the vmPFC and
Guided imagery MDD Huang et al. (2014) 23 (unmedicated)
5 weeks of treatment ACC
PET
Brody et al. (2001) 39 12 weeks of CBT Increased activity in the dlPFC and dACC
[145] (unmedicated) (comparison group Decrease in activity in the vACC and anterior insula
received paroxetine)
PET
Reduced activity in lateral PFC, caudate, thalamus, left
Interpersonal Brody et al. (2001) 24 12 weeks of IPT
MDD ACC Increased activity in left temporal lobe
psychotherapy (IPT) [146] (unmedicated) Comparison group received
paroxetine
SPECT
Up to 16 hour-long weekly
Martin et al. (2011) 10 (unmedicated) sessions Increased blood flow in right BG and right PCC
(comparison group was
treated with venlafaxine)
Goodman et al. 11 fMRI
Decrease in amygdala activation to unpleasant images
(2014) (unmedicated) 12 months of DBT
Dialectical behavioral fMRI
BPD 8
therapy (DBT) 12 weeks of DBT; amygdala Increased connectivity between vmPFC and amygdala
Paret et al. (2016) (all patients on
neurofeedback (NF) (did not persist without NF component)
medications)
incorporated for 4 sessions
17
18
Table 3: Description of psychotherapy and neuroimaging studies: psychodynamic psychotherapy.

Number of patients
(intervention group)
fMRI Decreased limbic and increased vPFC and OFC activity
PD Beutel et al. (2010) 9
4 weeks (inpatient setting) Parameter was emotional linguistic go/no-go task
fMRI Decrease in amygdala, dmPFC, and sgACC
Buchheim et al. (2012) 16 (unmedicated)
15 months hyperactivity
PET
Greater binding of 5-HT1A in the medial PFC and in
Karlsson et al. (2010) 8 (unmedicated) 16 weeks of therapy
the OFC
Comparison group received fluoxetine
PET
9 (treatment completers; all 16 weeks of dynamic therapy using the
Roffman et al. (2014) Decrease in metabolism of right insula
on antidepressants) Core Conflictual Relationship Theme
MDD manual
1
(unmedicated)
SPECT
Viinamäki et al. (1998) (Likely comorbid SERT density normalization within the mPFC
Weekly therapy for 1 year
borderline personality
disorder)
Decrease in BG and amygdala hyperactivity to
18 fMRI
Wiswede et al. (2014) operationalized psychodynamic diagnostics (OPD)
(unmedicated) 8 months
sentences
5 enrolled
SPECT
BPD Lai et al. (2007) (2 completed) Increased perfusion in frontal cortical areas
Weekly for 16 months
(unmedicated)
Psychiatry Journal
responses to emotional faces [262–264]; posttreatment effects lateral PFC, informing a more affectively informed and less
demonstrated a decrease in activation of the amygdala [262, cognitively controlled circuitry. In the cited study, treatment
263], as well as within the sgACC (which can inform dlPFC also resulted in a decrease in activation of the vmPFC, which
activity) [263], with more ventrally favored pathways being may suggest a more integrated form of decreasing subcortical
recruited; one study showed posttreatment activation of the hyperactivity by deploying other areas of the extinction
ventrolateral PFC (vlPFC) when exposed to angry faces (this circuitry.
area also aids in top-down control of the amygdala) [264].
Stimulus processing in anxiety disorders can be excessively (2) CBT for Major Depressive Disorder. CBT is arguably
influenced by amygdala input; CBT, through response pattern the most well-validated form of psychotherapy for MDD
recognition and gradual incorporation of contextual data into (showing potential effectiveness over 50% of cases) [261],
one’s appraisal of the environment, increases hippocampal though evidence has supported combination treatment (with
activation, allowing for a more nuanced and cognitively either medication or other modalities of therapy) [269, 270].
informed processing to take place [265]. There are many studies which have gauged predictive and
SAD can be considered a condition which factors in outcome findings relating to psychotherapy for MDD, and the
both the cognitive/distal and subcortical/proximal elements effects of CBT on neural circuits in MDD are multifaceted
of anxiety and fear responses, as the reality of exposure and still an area of active research. There is some level of
occurs alongside pronounced ruminative processing. The controversy surrounding how activity in given areas fits into
importance of the cognitive component is of particular rele- the framework of this condition, and this will be discussed
vance when reviewing results in the literature for the efficacy below.
of CBT, as there have been some varying findings, par- As mentioned, changes in emotional stimulus discrimi-
ticularly pertaining to subcortical elements. Attenuation of nation in the amygdala and portions of the ACC, decreased
enhanced dACC-amygdala and dorsomedial PFC- (dmPFC-) input from the hippocampus, alterations in reward process-
amygdala connectivity [226] was demonstrated in one CBT ing, and biased PFC recruitment are relevant in the clinical
study, suggesting a more flexible top-down control. In presentation of MDD. As such, the patterns of PFC, cingulate,
contrast, another study showed that amygdala reactivity to and amygdala-hippocampal activation are the prime regions
negative self-beliefs remained consistent over time in the of interest throughout the studies analyzed. As noted in
treatment group [266]; there was an increase in areas of anxiety disorders, CBT can result in a strengthening of
the dorsal PFC (namely, dmPFC and dlPFC). The authors contextual appreciation of stimuli, with normalization of the
stressed the importance of these areas specifically in cognitive amygdala-hippocampus activation pattern and less amygdala
reappraisal, as opposed to areas of the brain involved in fear hyperactivity when exposed to emotional faces [240] (though
extinction. Another individual CBT study assessed the effects it is important to highlight some level of functional het-
of treatment on emotional responsivity to social evaluation erogeneity within the amygdala, as evinced by therapeutic
[267]. Interestingly, as with the study before, improvement response leading to heightened activity to implicit processing
in negative emotions when reappraising social criticism was of emotions) [271]. Modification of activation patterns with
associated with activation in mainly cognitive as opposed CBT also occurs in other areas involved with processing
to more effectively attuned cortical areas as a result of the of emotionally salient stimuli, such as the precuneus and
treatment. Increased hippocampal activation and a decrease inferior parietal lobule [272]. The trend towards activating
in dysfunctional IFG-hippocampal connectivity was noted more ventral portions of the cingulate and PFC has also been
with therapist-guided CBT in panic disorder patients (as demonstrated with CBT. One PET study comparing CBT to
compared with self-guided treatment), suggesting cognitive venlafaxine showed that treatment response correlated with
reframing and increased contingency encoding may be facil- a decrease in dorsal areas of the cingulate cortex (namely, the
itated by the therapeutic dyad [144]. PCC) and with a metabolic increase in the anterior portion
With regard to more proximal fear response patterns, of the sgACC and vmPFC [273], indicating greater top-down
CBT has been shown to decrease limbic, paralimbic, and PAG regulatory function (this is particularly relevant given that
hyperactivation in a public speech task, with maintenance of activity in the sgACC has been associated with depression
effects at one-year follow-up [236]; when exposed to a specific severity, as this area in MDD can show decreased volume)
phobic stimulus (e.g., a spider), CBT can additionally pro- [274]. The increase in mPFC activity has been replicated
mote a decrease in dlPFC and insula activation, highlighting elsewhere [241, 275]. Response to treatment has also been
the decrease in autonomic fear systems as well as activity in associated with a decrease in metabolism in the OFC [273,
areas implicated in disgust and shame. A decrease in insula 276], which may indicate an increase in flexibility in terms of
activity during fear processing was supported by an addi- the fixity of salience ascribed to stimuli, given that the OFC
tional study of spider phobia in patients undergoing group can contribute to establishing affectively biased perceptions
CBT with an exposure component [268]. In the treatment of [273]; in line with this, it has been hypothesized that the
PD, CBT has been shown to decrease activation within fear- increase in OFC activity in MDD is a compensatory mecha-
based networks (e.g., amygdala, anterior insulae, and dACC), nism owing to an attempt to regulate amygdala hyperactivity,
as well as promoting more harmonious circuit connectivity. given the decrease in sgACC/vmPFC regulatory mechanisms
The latter is exemplified by normalization of hyperactivation [274]. The decrease in dmPFC activity shown in this study
in the IFG [230], as well as greater connectivity between the [273] after CBT is also of relevance given that this corti-
latter and the amygdala, hippocampus, ACC, and medial and cal area is involved in self-referential aspects of emotional
stimulus processing, incorporating elements of ascribing activity with successful treatment, though again this may be
meaning to emotional experiences and recall of affect-laden adaptive.
past events, and again a decrease in activation may reflect With regard to the reward pathway, it has been mentioned
greater cognitive and self-assessment flexibility. Other dorsal that patients with MDD have difficulty predicting positive
cortical areas (e.g., dlPFC) have been shown to decrease their outcomes to potentially rewarding situations. One adolescent
excessive activity in response to treatment, in tandem with study of group CBT assessed response to treatment through
its effects on a reward paradigm [280]. Successful treatment
increased hippocampal and parahippocampal activity [276],
resulted in a decrease in bilateral amygdala, hippocampus,
again reinforcing the more harmonious PFC network as con- and sgACC activity. The authors associated the sgACC
textual input is allowed through revisiting ingrained thinking hyperactivity with predicting treatment response (see further
patterns. It should be noted that modification within cortical discussion regarding neural predictors of response later in
circuitry (without engaging limbic structures) can lead to this paper) and emphasized its role in erratic processing of
clinical change. In one study [272], there was a significant stimuli, which may lead to poor self-views and impaired
positive correlation between symptom improvement and left ability to appreciate positive stimuli. Behavioral activation
precentral gyrus activity, a brain region involved in successful therapy has also resulted in greater engagement of the VS and
response inhibition, which may be impaired in MDD [277]. precentral gyrus during anticipation of rewards and of the
Interestingly, in this study, there was not an observable OFC during reward feedback [281].
engagement in the amygdala, something which was felt to
be due to the cognitively effortful nature of accessing and (3) CBT for Posttraumatic Stress Disorder. The revisiting
working with dysfunctional thoughts, an activity which may of traumatically informed cognitive beliefs can be done
be more circumscribed to cortical areas; thus, this would through multiple therapeutic modalities (see further discus-
be one instance in which the “medialization” phenomenon sion below), many of which incorporate elements of CBT. The
(given the dorsal and lateral localization of the structure) and neurobiology of PTSD is marked by heightened activation
greater cortical-subcortical connectivity would be bypassed, of the amygdala-dACC network, as well as of the insula,
though still with clinically relevant effects. with little room for contextual hippocampal input. Successful
CBT has been shown to effect a decrease in hyperactivation
It does need to be emphasized that these different brain
within the amygdala [282], dACC, and anterior insula [283],
regions are not uniquely ascribed discrete functions, as our
allowing for enhanced cognitive appraisal.
understanding of functional connectivity has evolved. As
such, while certain patterns can be noted in the conditions (4) Dialectical Behavioral Therapy (DBT). Both BPD and
outlined, there may be variations depending on compen- ASPD, as mentioned, are associated with decreased function-
satory activation of other networks. One example of such ing of the vmPFC, interfering with empathic attunement and
is the parahippocampal gyrus in MDD. This brain area, as ability to safely regulate affective arousal when confronted
the hippocampus, is associated with episodic and contextual with social cues. DBT is an integrative approach which has
memory, assisting as well in the associative learning of pos- been gaining evidence in the treatment of BPD [284]; it
itively and negatively valenced experiences, and activation consists of both individual and group processes and integrates
is greater with novel as opposed to familiar tasks. Increased elements of CBT as well as mindfulness, aiding in distress
activity in this area in response to treatment may indicate tolerance, cognitive reframing, and interpersonal skills. In
incorporation of new information and modes of thinking, addition to the neural changes deriving from cognitive
linking contextual input with new modes of understanding reframing and working through interpersonal challenges (as
one’s cognitive schemas [276]. Parahippocampal activation described with CBT and IPT, resp.), mindfulness can be
can also be associated with dysfunctional attitudes and neg- associated with increased activity with more medial portions
ative beliefs; thus, in reworking these through CBT, activity of the PFC and ventral parts of the ACC [285], as well as
can be decreased in this area over time [272]. Sankar et a decrease in amygdala activation [286]. Neural findings in
al. posited that this occurred due to a decrease in extreme successful DBT have echoed these effects, showing increased
negative thoughts in the treatment group as well as an connectivity between vmPFC and amygdala (however, this
increased familiarity with the material being accessed (it only occurred with active neurofeedback incorporated) [287]
is of note that a similar decrease occurred in the control and a decrease in amygdala activation [288].
group, indicating this gradual assimilation of material and the Mentalization-based therapy has been shown to be help-
lessening of parahippocampal activity is functional) [272]. ful in both BPD and ASPD [289] and seeks to activate the
Another example relates to increased activity of dorsal areas vmPFC by attempting to access the mind of the other and
of the cingulate in response to treatment, such as the dACC assess the cognitive process which unfolds with this exercise.
and PCC (the latter also having reciprocal connections with To date, this author is unaware of neuroimaging studies which
the dlPFC; the reader is referred to the section on interper- assessed brain changes with this form of treatment, but it is an
sonal psychotherapy for discussion of increased activation exciting prospect for the future.
of the PCC) [276, 278, 279]; this finding may underscore
activation of dorsal PFC regions during CBT in order to 4.2.2. Other Psychotherapeutic Modalities. This section will
access and revisit more inflexible thinking patterns; thus, detail a number of different therapeutic modalities, with a
there is not uniformity in the finding of decreased dACC brief description of the treatment, the conditions for which it
is used, and the neurobiological effects seen with therapeutic correlated with a decrease in regional cerebral blood flow
success. Table 2 describes the findings relating to these (rCBF) in the right uncus (refer to the section on EMDR for
different forms of therapy. functional description of this structure); there seemed to be
conflicting finding regarding activation of the middle frontal
(1) Eye Movement Desensitization and Reprocessing (EMDR). gyrus (MFG; both superior and middle FG are part of the
EMDR has been gaining significant ground in the PTSD lit- dlPFC). The authors highlighted how there are conflicting
erature [290]. It allows for recall of difficult/traumatic images findings in the literature regarding the MFG and how greater
(at times with the aid of a script) while there is continued or lower activation may depend on the script utilized.
sensory input. An MRI study utilizing EMDR described
the effects of 12 weeks of treatment [291]. In response to (4) Interpersonal Therapy (IPT). IPT is a form of psy-
treatment, there was a bilateral volumetric increase in the chotherapy which happens in a stepwise approach to aid the
hippocampus, showing enhanced ability to process traumatic individual in terms of understanding how to adapt to certain
memories with greater contextual input and aiding with fear life events which may be informing their depressed mood.
extinction. The uncus (BA 36) is a portion of the parahip- The main topics addressed include unresolved grief, role
pocampal gyrus and has a role in repetition of stimuli that conflict, role transitions, and interpersonal deficiencies [296].
have affective salience, as well as in the processing of defense The studies discussed in this section will refer to management
responses to perceived threat; successful EMDR has been of MDD.
shown to decrease tracer uptake in this area, indicating Retrieval of autobiographical memories may favor more
downregulation of heightened responsiveness [292]. dorsal areas of the cingulate cortex, and this may be a factor
in the neural changes noted with IPT. There is increased
(2) Prolonged Exposure (PE). PE, another treatment modality activity in the dACC and PCC noted in IPT responders
employed in PTSD [203], consists of a combination of imag- [145, 279], though subsequent activation of the dlPFC has
inal exposure (recounting the traumatic experience) and in been inconsistently reported [146, 279]. The PCC is an area
vivo exposure (confrontation of traumatic reminders which involved in retrieval of episodic memory, and increased
had been avoided); this occurs as a manner of attempting to activity may indicate an enhanced ability to access thought
allow cognitive restructuring and to extinguish conditioned and improve executive functioning [297]. As mentioned,
fear responses associated with triggers. Top-down control the PCC activation pattern differs from that described by
of subcortical hyperactivity permits for fear extinction and Kennedy et al. (2007) with CBT [273]; the reasons for this are
consolidation of more adaptive associations. Two studies not entirely clear, though the function of this area with pain
highlight an important contrast in terms of how this can take perception (which may have a component of painful affect
place in response to PE. A study utilizing cognitive restruc- retrieval), as well as more involved discussions in IPT relating
turing with imaginal exposure utilized processing of fearful to active life role transitions with the component of grieving
faces to gauge treatment response [293]. Decrease in CAPS (as opposed to the more cognitively based technique of CBT),
scores correlated with an increase in rACC activity and a may have some relevance. Indeed, the PCC is involved in
decrease in bilateral amygdala activity, demonstrating the remembering familiar individuals in one’s life as well as in the
greater inhibitory activation of this network during fear neurobiology of grief and bereavement processes [298, 299].
processing. Another study employing a 10-week PE protocol
showed that fear extinction recall posttreatment was asso- 4.2.3. Psychodynamic Psychotherapy. Psychodynamic psy-
ciated with a decrease in rACC activation and increased chotherapy is essentially a form of insight-oriented treatment,
activity in the mPFC [294]. The rACC works in tandem allowing patients to access origins of conflicts and understand
with the vmPFC and sgACC in regulating the fear response; their sense of self, defensive structures (including efforts
however, it has a function of monitoring external cues [295], to suppress emotional responses), and present interpersonal
something which can be more or less adaptively activated functioning in light of early life experience. This is integrated
in individuals, depending on the surrounding structures’ with an understanding of real-time dynamics with the thera-
connection to subcortical areas, and it would seem there is pist, and an appreciation of transference-countertransference
not a straightforward correlation with symptom response in factors can help illustrate the internalized relationship tem-
PTSD, given the disparate findings regarding this area in the plates the patient may feel compelled to reenact. The latter
two studies mentioned. elements are conceptually important given the empathic
attunement element of the treatment (despite some level of
(3) Brief Eclectic Psychotherapy (BEP). BEP includes a number technical variation within schools of analytic thought), as this
of different technical elements, including imaginal exposure may engage more ventral areas of the PFC and aid in decreas-
and cognitive restructuring, in addition to some elements ing maladaptive dlPFC activity as well as amygdala hyperac-
of psychodynamic therapy and a farewell ritual when the tivity. In MDD, psychodynamic therapy promoted decreased
treatment is complete. BEP can be utilized for treating PTSD, activation of the dorsally biased bottom-up network, with
and there is a technical overlap with some elements of mitigation of subcortical and limbic hyperactivity [300–303],
PE, given the exposure and cognitive components of the a decrease in sgACC hyperactivity (an area involved in poor
treatment. A study examining the effects of BEP on PTSD self-esteem, guilt, and repression of emotions) [300, 304],
patients assessed their ability to process traumatic material as diminished activity in dorsal areas of the mPFC (associ-
outlined in a script they prepared [253]. Successful treatment ated with ruminative self-referential thought) [300, 305],
increased activity in vPFC [302], and normalization of SERT may indicate greater recruitment during interventions which
binding within medial portions of the PFC (as noted in require modulatory network engagement. Functional cou-
a SPECT study; PFC-amygdala top-down control relies on pling between areas of the ACC and amygdala may predict
serotonergic transporter integrity) [306, 307]. Modulation of whether an individual will benefit from CBT. Activating the
serotonergic transmission within the mPFC was shown in a dACC and a decreased dACC-amygdala coupling during
PET study assessing 5-HT1A density [308]. Psychodynamic a self-criticism task has been shown to predict sustained
therapy was associated with greater binding of 5-HT1A in response to treatment one year later [318]. In addition,
the mPFC and OFC, a finding which correlated with clinical increased pretreatment ACC-amygdala inhibitory coupling
improvement. As 5-HT1A is an inhibitory receptor, this may during fear conditioning has been associated with treat-
serve to counterbalance excessive glutamatergic tone in a ment response [148, 265]; interestingly, the l allele of the
number of brain regions; MDD has been associated with 5-HTTLPR polymorphism seems to be linked with this
greater 5-HT2 receptor density in the amygdala and PFC greater coupling posttreatment and may drive treatment
[309], which has also been linked with suicidal behaviors. response (though the allele per se does not seem to predict
Interestingly, the authors correlated the increase in 5-HT1A response) [178]. Carriers of the s allele display a decrease
binding with greater social functioning [310], replicating the in the ACC-amygdala connectivity [319], which may be
notion of heightened interpersonal attunement based on responsible for considerable variation in temperamental
experiencing an empathic other in a therapeutic setting. anxiety traits, and theoretically confer greater resistance
Effects of psychodynamic therapy have also been studied to therapeutic interventions. Another instance of genetic
in subjects with BPD [311]. Pretreatment imaging showed susceptibility to treatment nonresponse pertains to the
increased perfusion in limbic areas and diminished perfusion 5-HT1A rs6295 polymorphism; the G allele has been asso-
in the PFC; throughout the course of treatment, there was ciated with increased presynaptic autoreceptor expression
improvement in numerous clinical parameters (e.g., impul- (decreasing serotonin release due to inhibitory feedback)
sivity, self-injurious behaviors, therapeutic alliance, and and decreased postsynaptic receptor expression (potentially
adaptiveness of defense mechanisms), which correlated with leading to heightened glutamatergic drive and contributing to
an increase in perfusion in the frontal cortex, reflecting anxiety and depressive symptoms) [320]. The G/G genotype
enhanced limbic modulation through cognitive strategies. has been associated with fear generalization, heightened
Table 3 outlines the studies regarding psychodynamic awareness to threatening stimuli, and greater avoidance and
psychotherapy. It should be noted that the open-endedness escape behaviors, informed primarily by the amygdala and
of treatment lends itself to some replication challenges, and hippocampus [149]. Resistance to CBT was shown in G/G
there is a considerable difference in treatment length in some carriers, as indicated by continued amygdala hyperactivity in
of the studies mentioned. response to threatening and safety cues, as well as inability
to promote differential conditioning in ACC and insulae;
4.3. Neural Predictors of Treatment Response to Psychotherapy. G/G carriers also showed a decrease in self-initiated exposure
Extending the understanding that has emerged from neural behaviors, decreasing likelihood of benefitting fully from
changes which occur with successful courses of psychother- treatment [149].
apy, numerous studies have looked at activation patents In PTSD, pretreatment hyperactivity in amygdala and
within neural areas or circuits which could potentially predict ACC (both ventral and dorsal) was associated with treatment
an individual’s response to a particular therapeutic interven- nonresponse [282], which the authors hypothesized to indi-
tion. Areas which are actively engaged during treatment may, cate excessive affective discharge given the rapid presentation
through established pretreatment activation patterns, lead of stimuli, and question whether this is an adequate parallel
to further understanding of their role in psychopathology with PTSD, particularly given that this finding has been
and treatment response. Neuroimaging could therefore be an challenged by other studies, which emphasize the importance
ancillary method of tailoring treatment modalities to patients of engaging the ACC for adequate treatment response. Along
suffering from particular conditions. The reader is referred to the same lines, a decrease in limbic and paralimbic gray
additional reviews of the evolving use of this data in guiding matter density was a predictor of treatment response in an
treatment [312–314]. Table 4 outlines the studies investigating EMDR study [321]. As a corollary to the ability to appro-
predictors of psychotherapeutic response. priately control one’s responses to environmental stimuli,
As described in a previous section, individuals with PTSD subjects also showed greater response to CBT when
anxiety disorders can display heightened reactivity to threat. displaying higher pretreatment activation of frontostriatal
Hyperactivity in particular brain areas involved with threat networks during inhibitory control tasks; in contrast, poor
appraisal and response has been shown to positively pre- response was predicted by pretreatment requirement of a
dict response to CBT in the treatment of anxiety. This more widespread engagement of cortical and subcortical
applies to activity patterns in the amygdala (both hyper- and areas to perform a similar task; thus, a more contained
hypoactivity have been associated with predicting response) preexisting circuitry can be strengthened by psychotherapy
[147, 262], as well as increased activity in the dACC, hip- [322].
pocampus, and areas within the temporal and frontal lobes With regard to the predictive neuroimaging findings for
involved with one’s reaction to threatening stimuli [147, 315– the use of CBT for MDD, findings in the literature have at
317]. As these regions show changes over the course of times been contradictory, and further research efforts seem
treatment, it is hypothesized that higher levels of activation warranted. Despite hyperactivity in the amygdala being
Table 4: Description of psychotherapy and neuroimaging studies: predictors of therapeutic response.
Modality of
Diagnosis Study (including design if not previously outlined) Predictors of response
psychotherapy
Ball et al. (2014) Greater activation in hippocampus during maintenance of emotional response to
Psychiatry Journal
48 patients (25 GAD, 23 PD), all unmedicated negative images

CBT GAD fMRI Greater activation in anterior insula, superior temporal gyrus, supramarginal gyrus,
10 weekly sessions of CBT and superior frontal gyrus during cognitive reappraisal
McClure et al. (2007) Pretreatment amygdala hyperactivity
Greater pretreatment activation to angry versus neutral faces in portions of the
Doehrmann et al. (2013)
occipitotemporal cortices
Increased pretreatment activity to threat in the superior and middle temporal gyri
Klumpp et al. (2013)
and in the IFG. Hyperactivation to fearful faces in dmPFC, OFC, and dACC
[147] Increased pretreatment activity (in the presence of emotional faces) in the dACC
fMRI and dmPFC
21 patients (unmedicated except for 2 on bupropion) Decreased pretreatment amygdala and mOFC activity during emotion processing
12 weekly 60-minute sessions
CBT SAD
[148]
Greater pretreatment bilateral amygdala-pgACC connectivity
fMRI
21 patients (unmedicated except for 2 on bupropion)
12 weeks of CBT
Mansson et al. (2015)
Pretreatment dACC activation and lower dACC-amygdala coupling during
fMRI/support vector machines (SVM)
self-referential criticism task (92% balanced accuracy)∗ predicted sustained
26 patients (8 medicated)
response one year later
13 weeks of Internet-delivered CBT
Lueken et al. (2013) Greater pretreatment coupling between ACC and amygdala
Reinecke et al. (2014) Increased pretreatment activation in bilateral insulae and left dlPFC during threat
fMRI processing
CBT PD/AG 14 unmedicated patients with PD Increased right hippocampus gray matter
4 sessions of CBT
Straube et al. (2014) Nonresponse associated with heightened amygdala reactivity before and after
[149] treatment (informed by 5-HT1A rs6295 polymorphism G/G genotype)
Costafreda et al. (2009)
Response to treatment (gauged by response to sad faces) predicted by activity in the
16 unmedicated patients
ACC, superior and middle frontal cortices, paracentral cortex, superior parietal
fMRI
cortex, precuneus, and cerebellum
16 sessions of CBT
Crowther et al. (2015)
CBT MDD 20 unmedicated patients Pretreatment connectivity of the insula with the right medial temporal gyrus and
Resting-state functional connectivity MRI between the left intraparietal sulcus and OFC
Average of 12 sessions of BATD
Pretreatment activity in the dACC comparable to healthy controls predicted
Fu et al. (2008)
response
23
24
Table 4: Continued.
Modality of
psychotherapy
Konarski et al. (2009)
Nonresponse associated with pretreatment hypermetabolism the interface of the
PET
pgACC and sgACC
16 sessions of CBT
Comparison group was on venlafaxine
Mackin et al. (2013)
Nonresponse associated with thinner bilateral PCC and parahippocampal cortex,
22 patients (not receiving antidepressants)
left paracentral, cuneus, and insular cortices, and right mOFC and lateral occipital
MRI
cortex
12 weeks of CBT
McGrath et al. (2014)
82 total patients (unmedicated prior to starting trial)
Nonresponse associated with pretreatment hyperactivity in the subcallosal cingulate
PET
and in the superior temporal sulcus
12–24 weeks of CBT and/or antidepressant
(escitalopram) treatment
Increased pretreatment vmPFC and dlPFC activity predicted response. Parameter
Ritchey et al. (2011)
analyzed was response to pictures of different affective valence
Siegle et al. (2006)
14 unmedicated patients Response to treatment was predicted by low sgACC reactivity and high amygdala
fMRI reactivity to negative words
16 sessions of CBT (12 weeks)
Pretreatment sgACC hyperactivity to positive (versus negative) stimuli predicted
Straub et al. (2015)
response
Thompson et al. (2015)
60 patients (59 years and older; 44 completed study;
Decrease in activation in left inferior frontal triangle and right superior frontal
83% on at least one medication, though type not
gyrus
specified)
Increase in activation of right middle frontal gyrus and left superior frontal gyrus
fMRI
12 weeks of CBT
Walsh et al. (2016)
During anticipation phase, response was associated with: greater caudate-dACC
and caudate-rACC connectivity; greater right putamen-right OFC connectivity;
fMRI
decreased connectivity between right mPFC and dACC; and decreased connectivity
Up to 15 BATD sessions (average of 11.67 weekly
between left putamen and the subcallosal cortex
sessions)
Pretreatment decreased activity in vACC during self-referential information
Yoshimura et al. (2014)
processing
Pretreatment hyperactivity in amygdala, vACC, and dACC was associated with
Bryant et al. (2008)
nonresponse
Falconer et al. (2013)
CBT PTSD 13 patients Treatment response was predicted by higher pretreatment activation of
(6 on stable doses of SSRIs) frontostriatal networks (vlPFC, OFC, mPFC, and dorsal striatum) during inhibitory
fMRI control tasks (this study employed Go/No-Go task)
8 weeks of CBT
Psychiatry Journal
Psychiatry Journal
Table 4: Continued.
Modality of
psychotherapy
Buchheim et al. (2012) Increased pretreatment activity in the sgACC may predict response
Psychodynamic
MDD Pretreatment right precuneus metabolism (significantly higher in treatment
psychotherapy Roffman et al. (2014) completers; correlated also with psychological mindedness)
Guided imagery MDD Huang et al. (2014) Increased pretreatment regional homogeneity within the dACC
Nardo et al. (2010)
20 patients (15 completed EMDR); unclear if patients
were medicated or not (it was not an exclusion
EMDR PTSD Decreased gray matter density in limbic and paralimbic cortices
criterion)
MRI
Five 90-minute sessions
∗
Balanced accuracy is a mean of sensitivity and specificity.
25
described in MDD, this has not been a consistent region of this area can undergo, as mentioned, different activation pat-
interest (ROI) in studies assessing neurobiological change terns posttreatment [273, 280, 332]. Interestingly, increased
with treatment. Network remodulation on a “cortico- activity in the sgACC may predict response to psychody-
cortical” level may be more salient in assessing the effects namic therapy in depressed patients (activity which lessened
of CBT for depressed patients [323], given the rumina- over the course of treatment) [300]. Interpretation of this
tive and negative thought patterns that emerge (different finding is somewhat conjectural, though given the variable
from anxiety and trauma-related disorders, in which the nature of technique in psychodynamic therapy, preemptively
immediately threatening component is of prime concern active engagement of sgACC-limbic networks may be more
and in need of attention and active cognitive reworking adaptive depending on the material that is revisited. In
to promote symptom improvement). Though subsequent a study utilizing the Core Conflictual Relationship Theme
top-down influence will be paramount in modifying insula (CCRT) manual to guide psychodynamic psychotherapy,
and amygdala-based negative salience of environment and treatment was associated with a decrease in insula activation
self, predictive factors regarding treatment outcome seem [303]; in addition, precuneus activity prior to therapy was
to lie more within PFC and ACC patterns of activation associated with greater psychological mindedness (associated
[324], and dysfunctional PFC-ACC can be responsive to CBT with modest predictive value in dynamic therapy) [333]; both
[325]. Amygdala hyperactivity is mitigated with treatment, areas are associated with self-attributional beliefs; thus, being
but it is not a consistent predictor of response to CBT in able to realistically access one’s understanding of internal
subjects with MDD. Greater pretreatment activation of both responsibility for external events (balanced between anterior
dL and vmPFC areas is predictor of successful treatment and posterior portions of the precuneus) may help [334], par-
outcomes [241, 326]. Activity in these areas would allow for ticularly in this model of therapy, which reworks problematic
individuals to, respectively, engage in cognitive reappraisal interpersonal relationships. Importantly for psychodynamic
(a function which can be impaired in MDD) [326] as well therapy, the precuneus is involved in several dimensions of
as allowing for more active vmPFC-amygdala control over self-awareness, including taking the first-person perspective,
the course of treatment, limiting subcortical input which episodic memory, and self-agency [335]. In addition to its
could make the work overwhelming or distressing, hindering implications in dynamic therapy, thinning of the precuneus
progress. There are conflicting findings in the literature with can predict nonresponse to CBT in late-life depression [336].
regard to predictive factors relating to activity within the The dACC has also been implicated in predicting
different areas of the ACC, as functional divisions are not response to CBT. Fu et al. (2008) showed that pretreatment
entirely clear. Within the subdivisions of the ventral portions activity within the dACC which was comparable to healthy
of the ACC, the “affective” and “cognitive” functions may controls predicted a successful therapeutic response [240],
at times be less clear-cut, and it has been hypothesized which the authors correlated with involvement of the area in
that the pregenual cingulate is something of a watershed tasks associated with potential loss of reward; thus, normal
area [327]. This overlap can be appreciated with regard to activity in the midst of a major depressive episode may be an
the dlPFC and its connectivity to both rACC [Brodmann indicator of resilience. While the dACC may be implicated
area (BA) 24] and sgACC (BA 25). Treatment nonresponse in ruminative and excessive cognitive control, increased
has been associated with a decrease in dlPFC metabolism dACC-dlPFC connectivity (akin to increased rACC-dlPFC
and decreased activity in the rACC [273, 328]; this may coupling) may be adaptive in the task of engaging in actively
reflect difficulty accessing executive functioning regions of reworking modes of thinking in CBT, allowing for greater
the brain as well as top-down regulatory areas, making it treatment benefits. Areas of the cingulate and PFC are also
difficult to engage in the process inherent to CBT, particularly implicated in reward processing (which may serve as models
working with distorted cognitive patterns. In MDD patients, for anhedonia), in particular relating to their connectivity
the sgACC has been shown to have decreased gray matter with striatal regions. Two studies utilized behavioral acti-
volume and metabolic activity [329]. Low baseline sgACC vation treatment for depression (BATD), which is geared
activity and deficient sgACC-amygdala regulatory coupling specifically towards having patients interact in a sustained
may inform negatively ruminative thought patterns [330], manner with positively reinforcing stimuli, attempting to
and it has been hypothesized that CBT will be most useful in ameliorate reward processing dysfunction [337, 338]. In one,
these cases because the inhibitory control can be enhanced response to treatment was predicted by greater connectivity
through successful therapy [330]. Hyperactivity in a region between the caudate-dACC and caudate-rACC, as well as
between the rACC and sgACC has been associated with by greater connectivity between right putamen and right
resistance to both CBT and antidepressant response [331, OFC (refer to Table 4 for additional findings). Within the
332]. In effect, response to CBT seems to be favored in reward paradigm, the dACC is associated with estimating
patients with a stronger rACC-dlPFC and a weaker sgACC- potential values of rewards and cognitively gauging whether
amygdala pretreatment activity, suggesting that revisiting to consider a determined action [337]. Thus, as alluded to
maladaptive schema indeed requires active revisiting of one’s earlier, selective hyperactivity within the dACC may facilitate
cognitive distortions, and enhanced top-down control may cognitive reworking in MDD while maintaining active ability
be more important with regard to the vmPFC. However, it to process reward, predicting better outcomes. In addition to
is not entirely clear whether circumscribed functions and connectivity with basal ganglia, enhanced connectivity of the
responses of the sgACC can be promoted, in particular as OFC (involved with assigning salience to stimuli, as well as
with reward processing and feedback) with cortical regions 5. Conclusions

was also shown to be a predictor of treatment [338].
This brief discussion highlights that certain preexisting This paper focused on multiple aspects of environmental
network activation, while contributing to some dimensions input on epigenetic and neural circuitry components. It
of psychopathology, may also be adaptive in allowing for highlighted how early life adversity can lead to repression
optimal engagement in therapy and maximizing the response of key genes through methylation processes and to the
to treatment. template of concretized forms of thinking which can be
internalized as default modes of negotiating the environment.
4.4. Interpersonal Component as Modifier of Neural Circuitry. The reparative effects of the latter will be contingent on
Though intuitive, one aspect of psychotherapy is the funda- the presence of a nurturing other who can allow for the
mentally dyadic nature of this treatment modality. In keeping patient to feel a level of attunement which may have been
with the argument put forth by this paper, early life adversity lacking earlier in life. The purported lack of containment
and lack of dyadic attunement can create a neural circuitry by the primary caregiver as a child can have long-lasting
which effectively diverts one from accessing the intensity of effects on genetic, neuroendocrine, and circuitry levels and
the affective response and turns to more cognitive control inform multiple arenas of psychopathology. However, there
mechanisms as a default form of coping, in effect evading a is notable plasticity within areas of the CNS, facilitated by
more integrated manner of thinking. This template can lead gene malleability promoted by demethylation, something
to subsequent psychopathology and more ingrained view which can be observed with positive environmental input
of self and others, ruminating on themes of worthlessness,
(e.g., exercise, positive social environments, and psychother-
isolation, and mistrust with regard to the intention of others.
apy), bolstered by the plastic effects of psychopharmacologic
Reactivity within subcortical areas tends to magnify these
agents (indeed, the epigenetic effects of medications are well
core beliefs, requiring modulation by higher cortical areas
recognized as a potential ancillary component to enhance
which may not be capable of effecting such change. Through
psychotherapy) [344]. As imaging and genetic research grows
the dyadic interaction of the psychotherapy setting, a new
in sophistication, predictors of treatment response (both
pattern of interpersonal relating can be fostered, one based on
pertaining to medications and psychotherapy) may allow for
empathic attunement and allowing for exploration of highly
more tailored approaches to patient care [314, 345]. There are
sensitive themes in a safe setting. The establishment of this
relationship can allow for a restructuring of these default still some conflicting findings in the literature which have
modes of responding, creating greater fluidity between dif- made some extrapolations somewhat tenuous, as resting-
ferent PFC areas, in particular accessing areas involved with state functional imaging can differ from more dynamic task
empathic responses (i.e., vmPFC), which also are instrumen- assessments; also, the expression of certain genes which
tal in controlling subcortical areas which impose a bottom- control circulating stress hormones and those promoting
up, affectively driven response to stimuli. Interestingly, one neuroplasticity do not always show straightforward corre-
of the trending modalities for treatment of PTSD is the lations with symptom response. This in part stems from
adjunct use of methylenedioxymethamphetamine (MDMA) inconsistent findings regarding the influence of cortisol on
in addition to psychotherapy; one of the principles behind memory consolidation, as well as the complicated relation-
such an addition is to facilitate the “empathogenic” abilities ship between neurotransmitters and psychopathology (e.g.,
of the patient, allowing for greater interpersonal comfort and the relationship between BDNF and the serotonergic system),
thus “open up” about traumatic experiences without over- something which is strongly underlined by the concept of
whelming anxiety or vigilance about the therapist [339, 340]. differential susceptibility. The continued input of the envi-
A good degree of controversy surrounds generalizing this ronment is paramount in determining how risk or resilience
viewpoint across psychotherapeutic modalities, as discussed. factors will translate as such, inviting our field to revisit such
One of the more consistent forms of therapy in which this dichotomous concepts and appreciate the dynamic and ever-
medialization is appreciated is psychodynamically oriented evolving nature of gene-environment interactions. A truism
psychotherapy. The focus on the interpersonal relationship has become the importance of therapeutic rapport, and
in the room, honing in on transference dynamics may the progressive medialization of neural circuitry observed
contribute to the more consistent findings of medial structure with numerous forms of psychotherapy found by researchers
activation, given the “real-time” interpersonal component assessing responses in a number of psychiatric conditions
which is intrinsic to the technical approach. illustrates that the empathic interpersonal element is a vital
As an interesting contrast, meditation practitioners (who component to treatment which transcends technique, allow-
engage in an inherently solo practice) show a deactivation ing for the safety and novelty of a containing setting to
of the amygdala through increased activity in the dlPFC and provide the patient with means to reach into the depths of
decreased activity in the mPFC, indicating that heightening their conflicts and not feel alone.
attention, self-monitoring, and executive/cognitive control
can decrease one’s visceral response, in a manner disengaged
from the interpersonal circuitry discussed before [341, 342]. Conflicts of Interest
A similar phenomenon has been observed in practitioners of
mindfulness, which borrows some of the same principles of The author declares that there are no conflicts of interest
meditation [343]. regarding the publication of this paper.
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Hindawi

Correspondence should be addressed to Christopher W. T. Miller; [email protected]

Received 10 December 2016; Accepted 11 April 2017; Published 25 May 2017

Academic Editor: Vaishnav Krishnan

1. Introduction equivalence [1, 2], has garnered considerable controversy [3],

Information regarding Hippocampal activation:

Preferential activation Preferential activation

Modality of psychotherapy Diagnosis Study (intervention Design Treatment effects of psychotherapy

Table 3: Description of psychotherapy and neuroimaging studies: psychodynamic psychotherapy.

48 patients (25 GAD, 23 PD), all unmedicated negative images

with reward processing and feedback) with cortical regions 5. Conclusions

References [19] K.-P. Lesch, D. Bengel, A. Heils et al., “Association of anxiety-

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