Central Neural Correlates of Generalized Anxiety Disorder: A
Systematic Review
Bachelor Degree Project in Cognitive Neuroscience Basic level 22.5 ECTS
Spring term 2021
Student: Alexandra Rundström Supervisor: Joel Gerafi
Examinator: Andreas Kalckert
Abstract
Generalized anxiety disorder (GAD) is a prevalent anxiety disorder that is characterized by persistent excessive worrying that is often difficult to control. The pathology of GAD has been associated with abnormal neural activity and functional connectivity. This systematic review has examined the central neural correlates of GAD which are the prefrontal cortex (PFC), the anterior cingulate cortex (ACC) and the amygdala and how activation and functional
connectivity in these brain areas differ between patients with GAD and healthy controls. This review also investigated how abnormal functional connectivity and activation in these brain regions relates to worry which is the most prominent psychological symptom in patients with GAD. A systematic review was conducted and seven original functional magnetic resonance imaging (fMRI) studies were included after a literature search on PubMed, Scopus and, Web of Science. The main findings from this review revealed decreased activation in the PFC and ACC and enhanced activation in the amygdala during the viewing of negative stimuli in patients with GAD. Identifying the neural correlates of GAD and how it relates to worry may provide improved treatment in the future such as developing more effective psychotropic drugs or improved psychotherapy. GAD has been associated with lower well-being and life satisfaction and may even be a risk factor for suicidal thoughts. One of the limitations from this review is that several of the included studies recruited patients with comorbidities and for that reason results from these studies cannot be generalized and applied to individuals with GAD.
Keywords: generalized anxiety disorder, prefrontal cortex, anterior cingulate cortex, amygdala, worry
Central Neural Correlates of Generalized Anxiety Disorder: A Systematic Review
Generalized anxiety disorder (GAD) is common in the general population and has a prevalence of 5 % which is the highest prevalence among all anxiety disorders, and is twice as common in females (Kolesar et al., 2019; Wittchen, 2002). According to Weisberg (2009), the prevalence seems to be highest in adulthood and the median age at onset is estimated to be 31 years which is the highest median age at onset compared to all other anxiety disorders.
The disorder seems to be more prevalent in Caucasians, individuals with low income, and people who have been divorced or separated (Morrison, 2014). Further, worry has been identified as the core feature of this disorder and is characterized by persistent exaggerated worrying that is often difficult to control. These individuals can for instance worry excessively about problems with work, health, school, or money, and are often unable to recognize the cause of their worry. Both physical and psychological symptoms can be found in individuals with GAD such as muscle tension, inability to rest or relax, irritability, loss of concentration, and problems with sleep such as insomnia (Morrison, 2014). GAD has been associated with impairments in everyday life such as social relationships or diminished work productivity which can lead to a significant economic burden (Henning et al., 2007; Wittchen, 2002).
The ability to regulate and control emotions is an essential skill for humans to behave appropriately in social interactions (Hilbert et al., 2014). It is also a significant component of well-being that some psychiatric disorders lack, such as GAD (Phelps & LeDoux, 2005;
Hilbert et al., 2014). Gross (2002) defines emotional regulation as the process when
individuals increase, decrease or maintain negative or positive emotions which either occur consciously or unconsciously. Since we humans live in a complex social and emotional society it is of great importance to be able to control and regulate our emotional responses (Decker et al., 2007). The prefrontal cortex (PFC) and anterior cingulate cortex (ACC) are structures in the brain that are associated with emotional regulation (Hilbert et al., 2014). Research with functional magnetic resonance imaging (fMRI) has indicated that enhanced neural activity in these brain regions correlates with worry in both healthy individuals and patients with GAD (Paulesu et al., 2010). However, abnormal activation such as reduced functional connectivity between the PFC, ACC and the amygdala seems to be associated with excessive worry which is the most prominent symptom of GAD (Hilbert et al., 2014; Paulesu et al., 2010). Abnormal activation such as reduced functional connectivity between these brain regions seems to be associated with emotional dysregulation, a term used to describe a person's difficulties in regulating emotional responses which are defined as a key feature of GAD (Decker et al., 2007). According to Behar et al. (2009), emotional dysregulation in individuals with GAD causes them to experience emotions more intensely compared to healthy individuals, especially negative emotions. Further, emotions often occur more easily and faster in
individuals with GAD, and they also tend to express their emotions more often, particularly negative emotions. Furthermore, some studies have indicated that worry severity seems to be associated with increased activation in the PFC. These findings are contradictory since most studies have demonstrated that the pathology of GAD seems to be associated with less prefrontal activation (Mochcovitch et al., 2014).
The amygdala is a structure in the brain that is associated with emotional processing and is particularly known for processing fear (Phelps & LeDoux, 2005). Increased activation in the amygdala has been demonstrated during the viewing of negative stimuli in patients with GAD compared to healthy controls (Mochcovitch et al., 2014). Abnormal activation in the amygdala such as enhanced activation is the most consistent findings in studies
investigating the neural correlates of GAD (Dong et al., 2019). However, contradictory to these findings, research has also indicated decreased amygdala activation in these patients compared to healthy controls when viewing aversive pictures (Hilbert et al., 2014). Research has also demonstrated that the amygdala has an important role in emotion regulation and inhibition (Phelps & LeDoux, 2005). Research with fMRI and emotional regulation tasks (e.g.
face emotion task) have revealed that during emotional regulation, the ACC and PFC inhibit the amygdala`s activation in healthy individuals compared to patients with GAD
(Mochcovitch et al., 2014). These findings indicate that healthy individuals are better at regulating the response to emotional stimuli which seems to be associated with less levels of anxiety in contrast to patients with GAD (Hilbert et al., 2014). Furthermore, several studies have demonstrated that patients with GAD showed less functional connectivity between the previously mentioned brain areas which have been associated with deficiencies in inhibition of amygdala activation which leads to increased activation in the amygdala (Mochcovitch et al., 2014). It seems that reduced functional connectivity between prefrontal areas and the amygdala correlates with anxiety severity in patients with GAD (Dong et al., 2019; Paulesu et al., 2010 ).
This systematic review aimed to examine and present the central neural correlates of GAD which are the PFC, ACC, and the amygdala and how activation and functional
connectivity in these brain areas differ between patients with GAD and healthy controls. This review also investigated how abnormal functional connectivity and activation in these brain regions relate to worry which is the most prominent psychological symptom in patients with GAD. Based on previous research, the hypothesis is decreased functional connectivity
between the PFC, ACC and the amygdala and that decreased connectivity between these brain regions are associated with worry in patients with GAD. Furthermore, increased amygdala activation in GAD patients during exposure to negative stimuli was also expected. Identifying the neural correlates of GAD and how it relates to worry may provide a better understanding of the maintenance and development of this disorder as well as improved treatment such as
developing more effective psychotropic drugs or improved psychotherapy (Hilbert et al., 2014). In health care, there is a high prevalence of these patients which has a major impact on society in terms of increased economic costs (Wittchen, 2002). According to Weisberg (2009), GAD has been associated with lower well-being and life satisfaction and may even be a risk factor for suicidal thoughts.
Methods Search Strategy
A systematic literature search has been conducted by one reviewer to collect secondary data to include in this review. This information has been analyzed and the most relevant findings are presented in the section results. Electronic databases: PubMed, Scopus, and Web of Science were used when searching for research articles by using the search string:
("generalized anxiety disorder" OR “generalised anxiety disorder”) AND (“prefrontal cortex”
OR PFC) AND (“anterior cingulate cortex” OR ACC) AND (amygdala) AND (“functional magnetic resonance imaging” OR fMRI). By using this search string a total of 114 articles were found, (n= 19) in PubMed, (n= 60) in Scopus and, (n= 35) in Web of Science, the last search was conducted on 12 Mars 2021. All the 114 articles were exported to the web tool Rayyan QCRI to detect duplicates and 30 duplicates were found and removed from the search process (Ouzzani et al., 2016). This tool was also used to record excluded and included articles throughout the search process.
Inclusion & Exclusion Criteria
The inclusion criteria for choosing research articles for the systematic review were the following. The studies needed to be written in English and published between the years 2009 and 2021. This time range was set in the literature search process after the author of this review found most of the relevant studies between 2009 and 2021. All the articles had to be original research whereas reviews and meta-analysis were excluded. Only studies that have compared the neural activity between individuals with GAD and healthy controls by using fMRI were included whereas studies that had used other neuroimaging techniques were excluded. Studies that have examined healthy individuals as a comparison group were also inclusion criteria when choosing articles for the review.
After the duplicates were removed, titles and abstracts of the 84 articles left were read by the reviewer and a total of 55 articles were excluded from the search process. Out of these, 20 articles were excluded for not being original research and 35 were excluded for not
evaluating GAD patients. The full texts of the remaining 29 articles were scrutinized by the reviewer. From those, eight were excluded for not using fMRI, seven for not measuring neural activation, and seven for not comparing GAD with healthy participants (n= 7). In total,
seven original articles were included and they were all written in English. All the included studies had compared neural activity in individuals with GAD and healthy controls by using fMRI and were published between the years 2010 and 2018.
Data Extraction
This review will present findings from seven original fMRI studies that show abnormal activation and functional connectivity in the PFC, ACC and the amygdala in patients with GAD. Abnormal activation and functional connectivity between these brain regions and how it relates to worry in patients with GAD will also be demonstrated.
Furthermore, this review will display differences in neural activation and functional connectivity in the previously mentioned brain areas between GAD patients and healthy controls.
Figure 1.
PRISMA 2009 Flow Diagram
Results
The final search resulted in seven studies and further details about the search process can be seen in Fig. 1. All the main findings from each study will be divided into three
subsections based on what the results demonstrated. The first section will present neural activation in the PFC, ACC and the amygdala and how activation in these brain areas differs between patients with GAD and healthy controls (Blair et al., 2012; Etkin et al., 2010;
Fitzgerald et al. 2017; Palm et al., 2011; Strawn et al., 2012; Yin et al., 2017 ). The other section will include data that compare functional connectivity between the PFC, ACC and the amygdala in GAD patients and healthy controls (Makovac et al., 2016; Yin et al., 2017). The last section will demonstrate how activation and functional connectivity between the
previously mentioned brain areas is associated with worry in individuals with GAD (Blair et al., 2012; Makovac et al., 2016). All the included studies in this review are summarized in Table 1, regarding information about the participants, the interventions, the comparison groups, and the outcome from each study.
Table 1
A summary of all the 7 included articles
Authors Participants Intervention Comparisons Outcome
Blair et al. (2012) Patients with GAD (n=17) Mean age: 36.1, SD: 11.75 Medication free
Emotion regulation task Healthy controls (n=18) Mean age: 33.4, SD: 9.65
Measure whole-brain blood oxygen
level-dependent (BOLD) response during
emotional regulation.
Etkin et al. (2010) n=17 GAD patients (n=11 females, n=6 males) Mean age: 31.5, SD: 9.9 Medication free
Comorbidity (n=8) Dysthymia (n=2) Social anxiety (n=3) Social anxiety and Panic disorder (n=2)
Social anxiety and Obsessive-compulsive disorder (n=1)
Emotional conflict task
n=24 healthy controls (n=18 females, n=6 males) Female: 18
Mean age: 36.5, SD: 11.8
Behavioral and neural measures to compare trial-by-trial
changes in conflict regulation.
Continued on the next page.
Authors Participants Intervention Comparisons Outcome Fitzgerald et al. (2017) n=30 GAD patients (n=18
females, n=12 males) Mean age: 27.20, range:
18-65 years Medication free No major
medical or neurologic illness
Comorbidity (n= 29) Social anxiety disorder (n=13) major depressive disorder (n=6), panic disorder (n=3), specific phobia (n=3), PTSD (n=2), and
obsessive-compulsive disorder (n=2)
Emotion regulation task n=30 healthy controls (n=23 females, n=7 males)
Mean age: 25.43, range:
18 to 65 years No major
medical or neurologic illness
Measure neural activity of emotional reactivity and regulation of reactivity.
Continued on the next page.
Authors Participants Intervention Comparisons Outcome Makovac et al. (2016) n= 19 GAD patients (n=17
females, n=2 males) Mean age: 29.58, SD: 6.93
Verbal induction procedure task
n=21 healthy controls (n=18 females, n=3 males)
Mean age: 28.67, SD: 9.45
Measure BOLD signal before and after induction of perseverative cognition (rumination, worry).
Palm et al. (2011) n=15 GAD patients (n=15 females)
Mean age: 34, SD: 13 Comorbidities (n=10) (social phobia, specific phobia, panic attacks).
Implicit face emotion task n=16 healthy controls (n=16 females) Mean age: 34, SD: 13 No history of mental health problems
Measure BOLD response during the processing of positive and negative facial emotions.
Strawn et al. (2012) n=10 GAD patients (n=6 females, n=4 males)
Mean age: 14.3, range: 11–17 years
Medication free
Continuous performance task with emotional and neutral distractors
n=10 healthy controls (n=6 females, n=4 males) Mean age: 13.3, range:
11-17 years
Measure BOLD signal during the viewing of emotional and neutral stimuli.
Yin et al. (2017) n=20 GAD patients (n=15 females, n=5 males)
Mean age: 15.7, range: 13 to 18 years
Medication free
Emotional valence evaluation task
n=14 healthy controls (n=8 females, n=6 males) Mean age: 15.5, range: 13 to 18
Measure brain activation during viewing of negative vs neutral stimuli.
Evaluation of Activation in the PFC, ACC and the Amygdala
A study published by Fitzgerald et al. (2017) examined the neural activity of emotional reactivity (viewing of negative images) and regulation of reactivity. This study recruited 30 GAD patients and 30 healthy controls who performed an emotional regulation task during an fMRI scan. All the participants were exposed to negative and neutral images and were
instructed to use a cognitive strategy (reappraisal) to decrease the negative affect during the viewing of negative pictures. Both groups were also instructed to attend to the emotional state induced by the negative stimuli. The results from this study displayed enhanced activation in the left amygdala in GAD patients during emotional reactivity compared to healthy controls (Fitzgerald et al., 2017). However, increased activation in the left amygdala was not present during regulation after exposure to aversive images (Fitzgerald et al., 2017).
Further, the results demonstrated no difference in neural activity between the groups during reappraisal (Fitzgerald et al., 2017).
Another study published in 2012 investigated the neural activity in GAD patients during emotional regulation (Blair et al., 2012). In their study, they examined 17 patients diagnosed with GAD and 18 healthy controls who performed an emotional regulation task.
These two groups were exposed to negative and positive pictures and were instructed to either downregulate (make the positive pictures less positive and the negative pictures less negative) or upregulate (make the positive pictures more positive and negative pictures more negative). The findings from this study revealed that patients with GAD demonstrated decreased activation in the dorsal anterior cingulate cortex (dACC) compared to healthy controls during emotional regulation (Blair et al., 2012). Furthermore, GAD patients exhibited reduced amygdala activation during the time they were viewing negative pictures (Blair et al., 2012).
Yin et al. (2017) study measured and compared differences in neural activity between patients with GAD and healthy controls during the viewing of negative VS. neutral stimuli.
This study tested 20 patients diagnosed with GAD and 14 healthy controls who were instructed to perform an emotional valence task. The two groups were exposed to affective images such as positive, neutral, and negative during the fMRI scan and were instructed to indicate the valence of these pictures (tell if the pictures were either positive, negative, or neutral). This was done by pressing a button with either the right index finger, right middle finger, or left index finger respectively corresponding to positive, neutral, or negative stimuli.
In the evaluation of negative stimuli, the results demonstrated enhanced activation in the ventral medial prefrontal cortex (vmPFC) in patients with GAD compared to the control
group (Yin et al., 2017). Furthermore, GAD patients also exhibited increased activation in the bilateral amygdala during the viewing of negative stimuli (Yin et al., 2017).
A study published by Palm et al. (2011) investigated the neural activity in GAD patients when they were exposed to both positive and negative facial expressions. They recruited 15 patients diagnosed with GAD and 16 healthy controls who underwent an implicit facial emotion task. Both groups were viewed with facial expressions (anger, disgust, fear, happiness, sadness, and neutral ones). The participants were instructed to decide whether the faces were female or male by pressing a button. The results indicated that GAD patients displayed reduced activation in the ventrolateral prefrontal cortex (VLPFC) compared to healthy controls during the viewing of fearful faces (Palm et al., 2011). The GAD group also demonstrated reduced activation in the right ACC when they were exposed to sad pictures compared to the control group (Palm et al., 2011). During exposure to angry faces, healthy participants displayed enhanced activation in the VLPFC whereas the GAD group exhibited no alteration in neural response (Palm et al., 2011). When individuals with GAD were
exposed to happy faces, decreased activation in the VLPFC, and left ACC were demonstrated (Palm et al., 2011). The primary findings from this study revealed that the GAD group
exhibited decreased activation in prefrontal regions to all emotional expressions, particularly to happy faces (Palm et al., 2011).
Etkin et al. (2010) study examined the emotional conflict adaptation by using a task that spontaneously induced regulation of emotional processing without giving the
participants explicit instructions (Etkin et al., 2010). In their study, they included 17 patients with GAD and 24 healthy controls who underwent an emotional conflict task. The
participants had to identify a facial expression (tell if the face was either happy or fearful). At the same time, they also needed to ignore an overlying emotion word such as “happy” or
“fear”. These words either matched with the facial expression, e.g. the word fear with facial expression fear (congruent) or conflicted, e.g. the word happy with facial expression fear (incongruent). Further, emotional conflict occurred when participants were viewed with for example a congruent trial followed by an incongruent trial which led to decreased reaction time in both GAD patients and healthy individuals. Whereas “emotional conflict adaptation”
occurred when e.g. an incongruent trial was followed by an incongruent trial which led to improved emotional conflict regulation in both groups. This means that the participants enhanced their ability to faster identify facial expressions which were demonstrated in increased reaction time. The findings from this study revealed that healthy participants exhibited greater activity in the dorsomedial prefrontal cortex (dmPFC) during emotional conflict compared to the GAD group which demonstrated less activation (Etkin et al., 2010).
This indicates that healthy participants were more able to adapt to emotional conflict
compared to the GAD group. However, during congruent trials, there was no difference in neural activation between the groups (Etkin et al., 2010).
Strawn et al. (2012) investigated the functional neurocircuitry of adolescents diagnosed with GAD with an age range of 13 to 18 years. This was done by measuring the BOLD signal when participants were exposed to emotional and neutral stimuli. They
recruited 10 adolescents with GAD and 10 healthy controls to their study which performed a continuous performance task. The participants were exposed to squares (baseline), circles (targets) and emotionally neutral pictures, and emotionally unpleasant pictures which were viewed randomly. The findings from this study revealed that GAD patients demonstrated increased brain activation in the left medial prefrontal cortex and the right VLPFC when they were exposed to emotional stimuli compared to healthy participants (see Fig. 2) (Strawn et al., 2012).
Evaluation of Functional Connectivity between the PFC, ACC and the Amygdala
A study published by Makovac et al. (2016) investigated the interplay between worry which is the core feature of GAD and autonomic dysfunction which were done by measuring the BOLD signal before and after induction of perseverative cognition e.g.rumination or worry. This study tested 19 patients with GAD and 21 healthy participants which underwent a verbal induction procedure with the purpose to induce perseverative cognition such as
ruminative thoughts or worry. The findings from this study revealed that before the induction patients with GAD demonstrated less functional connectivity between the right amygdala and the ACC compared to healthy controls (Makovac et al., 2016). Furthermore, patients with GAD exhibited increased functional connectivity between these brain areas after induction compared to the control group who demonstrated less connectivity (Makovac et al., 2016).
Evaluation of Worry
Only two studies in this review investigated how activation or functional connectivity between the PFC, ACC and the amygdala relates to worry in patients with GAD (Blair et al., 2012). Blair`s study investigated and compared neural activation in patients with GAD and healthy controls during emotional regulation (Blair et al., 2012). The findings from this study revealed that patients with GAD exhibited reduced amygdala activation during the evaluation of negative stimuli which seems to be associated with worry. Makovac et al. (2016)
demonstrated that patients with GAD exhibited less functional connectivity between the right amygdala and ACC compared to the control group during baseline in their study. However, after these patients had undergone an induction procedure task intending to induce
ruminative thoughts or worry, GAD patients demonstrated increased functional connectivity
between the amygdala and ACC compared to healthy controls who exhibited decreased connectivity (Makovac et al., 2016). According to Makovac et al. (2016) increased functional connectivity between these brain regions correlated with worry severity in patients with GAD.
Discussion
This systematic review has examined the central neural correlates of GAD which include brain areas such as the PFC, ACC, and the amygdala and how activation and functional connectivity in these brain areas differ between patients with GAD and healthy controls. This review also investigated how abnormal functional connectivity and activation in these brain regions relate to worry which is the most central feature of GAD.
Seven original fMRI studies have been analyzed and the results are partially
conflicting (Table 1). Further, the main findings from this review revealed that GAD patients exhibited enhanced activation in the amygdala during the viewing of negative stimuli e.g.
angry faces (Fitzgerald et al., 2017; Yin et al., 2017). Increased activation in the amygdala during exposure to different kinds of negative stimuli in individuals with GAD has been demonstrated in previous research (Mochcovitch et al., 2014). These findings have been shown in further studies as well and according to Dong et al. (2019), enhanced amygdala activation is the most consistent finding in studies investigating neural activity in patients with GAD. However, contradictory to these findings, one study from the review showed reduced amygdala activation in patients with GAD during exposure to negative stimuli (Blair et al., 2012). The same author, Blair et al. (2008) has demonstrated similar findings in previous research when individuals with GAD were viewed with fearful facial expressions.
The results from Blair et al. (2008) study are contradictory since the amygdala is particularly known for processing fear and is associated with enhanced neural activation when humans are exposed to fearful stimuli (Phelps & LeDoux, 2005). Furthermore, decreased activation in the amygdala in patients with GAD during the viewing of aversive pictures has been
demonstrated in further research as well (Hilbert et al., 2014). According to Hoehn-Saric et al. (2005), decreased amygdala activation has been associated with worry severity in healthy participants, thus, decreased activation in the amygdala in patients with GAD may be linked to worry. Furthermore, since the findings regarding the amygdala are a bit conflicting, the author of this review suggests that more research needs to be done to further evaluate how neural activation in the amygdala differs between patients with GAD and healthy individuals.
The findings from the evaluation of activation in the PFC and ACC were conflicting.
The main findings from this review revealed reduced activation in the PFC and ACC in GAD patients during the viewing of negative stimuli such as aversive images compared to healthy controls (Blair et al., 2012; Etkin et al., 2010; Palm et al., 2011;). Palm et al. (2011) revealed that patients with GAD exhibited reduced activation in the VLPFC and the left ACC during
the viewing of negative stimuli such as fearful and sad facial expressions. According to Palm et al. (2011), reduced activation in the previously mentioned brain areas seems to be
associated with problems in the interpretation of emotional and social experiences. These findings are in line with further research which has demonstrated that patients with GAD show dysfunction in emotional regulation (Mochcovitch et al., 2014). According to Hilbert et al. (2014), emotional dysregulation in patients with GAD can lead to problems in social interactions. Additionally, the findings from Palm et al. (2011) study also demonstrated decreased activation in the VLPFC, and the left ACC when patients with GAD were exposed to happy faces. Based on these results, it seems that individuals with GAD have problems with regulating both positive and negative emotions which is in line with how Gross (2002) defines emotional regulation. According to Gross (2002), emotional regulation can be described as the process when individuals increase, decrease, or maintain both negative and positive emotions. However, more research needs to be done to further evaluate if negative and positive stimuli generate the same neural activation in patients with GAD. Furthermore, contradictory to the previously mentioned results, two of the included studies in the review displayed enhanced activation in the PFC when GAD patients were exposed to emotionally unpleasant pictures (Strawn et al., 2012; Yin et al., 2017). According to Paulesu et al. (2010), it seems that increased activation in the PFC and ACC is associated with worry in both patients with GAD and healthy individuals. Additionally, further research has also indicated that worry severity seems to be associated with increased activation in the PFC in patients with GAD (Mochcovitch et al., 2014).
In the evaluation of functional connectivity between the PFC, ACC and the amygdala, Makovac et al. (2016) revealed that patients with GAD exhibited less functional connectivity between the ACC and the amygdala during baseline in the study. However, after induction of perseverative cognition such as worrying and ruminative thoughts GAD patients
demonstrated enhanced functional connectivity between these brain regions whereas healthy controls exhibited decreased connectivity (Makovac et al., 2016). These findings are
consistent with previous research which has demonstrated that the pathology of GAD seems to be associated with decreased functional connectivity between the PFC, ACC and the amygdala and that these patients use worry as a maladaptive cognitive avoidance strategy (Borkovec et al., 2004). This means that patients with GAD use worry as an attempt to regulate excessive psychological arousal associated with anxiety (Borkovec et al., 2004).
According to Borkovec et al. (2004), it seems that individuals with GAD use worry as a cognitive attempt to prepare themselves for bad events to happen or to prevent bad events from occurring. Furthermore, studies have demonstrated that decreased functional connectivity between the PFC, ACC and the amygdala correlates with anxiety severity in patients with GAD (Dong et al., 2019; Paulesu et al., 2010 ). These findings seem to be in line
with Borkovec et al. (2004), avoidance theory of worry in patients with GAD. Additionally, research has indicated that reduced functional connectivity between the previously
mentioned brain areas seems to be associated with excessive worry in individuals with GAD (Hilbert et al., 2014; Paulesu et al., 2010). These findings are contradictory since
Mochcovitch et al. (2014) has indicated that worry severity seems to be associated with increased activation in the PFC in patients with GAD. Furthermore, the findings from
Makovac et al. (2016) study may explain why research is inconsistent in studies investigating the functional connectivity between prefrontal areas and the amygdala. However, most studies have indicated that the pathology of GAD seems to be associated with less prefrontal activation (Mochcovitch et al., 2014). Furthermore, since worry is the main feature of this disorder, it is of great importance to further investigate how decreased functional
connectivity between the PFC, ACC and the amygdala relates to worry in these patients (Morrisson, 2014).
Furthermore, as mentioned in the introduction, research has demonstrated that reduced functional connectivity between the previously mentioned brain areas is associated with emotional dysregulation in patients with GAD (Hilbert et al., 2014; Mochcovitch et al., 2014). Research has revealed that during emotional regulation, the PFC and ACC inhibit the amygdala`s activation in healthy individuals compared to patients with GAD (Mochcovitch et al., 2014). These findings seem to indicate that healthy individuals are better at regulating the response to emotional stimuli which seems to be associated with fewer levels of anxiety in contrast to individuals with GAD (Hilbert et al., 2014). Furthermore, findings revealing dysfunction in emotional regulation have been consistent in studies investigating the neural correlates of GAD (Hilbert et al., 2014). Since we human live in a complex social and emotional society, it is of great importance to be able to control and regulate our emotional responses (Hilbert et al., 2014) However, patients with GAD seem to lack this ability leading to impairments in everyday life such as problems with social relationships (Henning et al., 2007; Hilbert et al., 2014; Wittchen, 2002).
This review hypothesized to find results that demonstrate decreased functional connectivity between the PFC, ACC and the amygdala and that decreased connectivity between these brain regions is associated with worry in patients with GAD. Increased amygdala activation in GAD patients during exposure to negative stimuli was also expected.
Even though findings from the seven studies were conflicting (Table 1), some are in line with what the review hypothesized to find.
Diminished work productivity is a common problem among patients with GAD which can lead to a significant economic burden (Henning et al., 2007; Wittchen, 2002).
Furthermore, GAD has been associated with lower well-being and life satisfaction and may even be a risk factor for suicidal thoughts (Weisberg, 2009). In health care, there is a high
prevalence of GAD patients which has a major impact on society in terms of increased economic costs (Wittchen, 2002). Therefore, it is of great importance to identify the central neural correlates of GAD and how activation and functional connectivity in these brain areas relate to worry since it may provide us with improved treatments in the future such as more effective psychotropic drugs or improved psychotherapy (Hilbert et al., 2014). Since the diagnosis of GAD is merely based on subjective symptoms, the author of this review
concludes that measuring it objectively may provide us with a much better understanding of the disease in the future which will hopefully lead to improved quality of life in these patients.
Limitations
Since worry is the most prominent symptom of this disorder, the reviewer expected to find more data explaining the link between abnormal neural activity and worry in GAD patients, however, the psychological symptom worry was not the main focus in this review.
Investigating worry specifically could be a next step and how it is associated with abnormal activation and functional connectivity in the PFC, ACC and the amygdala in patients with GAD.
Another limitation is that several of the included studies recruited patients with comorbidities and for that reason results from these studies cannot be generalized and applied to individuals diagnosed with GAD (Etkin et al., 2010; Fitzgerald et al., 2017; Palm et al., 2011).
Furthermore, the age range has been very broad regarding the participants from the included studies, therefore findings from this review cannot be generalized to a certain age (Table 1). Two of the included studies in this review had recruited participants under the age of 18 which could confound the interpretation of the results since the brains of these
individuals are not fully developed yet (Strawn et al., 2012; Yin et al., 2017). According to Dumontheil (2016), the brain undergoes both structural and functional changes during adolescence which leads to different brain responses and behaviors unique to adolescents.
The PFC is a structure in the brain that undergoes major changes during adolescence, e.g research has demonstrated that adolescence exhibited greater activation in the mPFC within the social brain compared to adults
(
Dumontheil, 2016). Furthermore, several studies have demonstrated that adolescents show greater amygdala activation than adults during exposure to emotional stimuli(
Dumontheil, 2016).The previously mentioned studies that had recruited participants under the age of 18 may also be an ethical issue since these individuals are not old enough to sign the informed consent by themselves for participating in the study.
Future Research
It would be beneficial for further research to compare GAD to other psychiatric disorders since comorbidity is very common among individuals diagnosed with GAD (Hilbert
et al., 2014). Such findings could bring better knowledge about comorbidity in patients with GAD (Blair et al., 2012). According to the author, a deeper understanding of comorbidity in these patients may lead to better treatments.
The findings from Makovac et al. (2016) study could be beneficial for future research when evaluating the treatment response in individuals with GAD. Therefore, the author of this review suggests that similar studies could be conducted to a greater extent in the future to get novel insights into how different kinds of medication and therapy affects neural activation and functional connectivity in patients with GAD.
Research has demonstrated that GAD is twice as common in females as men (Morrisson, 2014; Wittchen, 2002). However, the author of this review has not found any studies investigating the reason why the disorder is much more prevalent in females, therefore it would be of interest to further examine this question. According to the author, one reason why the disorder is more prevalent in females could be that females in general, are more willing to seek professional help for their symptoms than males are.
Conclusion
The systematic review has investigated the central neural correlates of GAD which includes brain areas such as the PFC, ACC and the amygdala and how activation and functional connectivity in these regions differ between patients with GAD and healthy individuals. Further, this review also examined how abnormal activation and functional connectivity in the previously mentioned brain areas are associated with worry in individuals with GAD. The main findings from this review revealed enhanced amygdala activation in patients with GAD compared to healthy controls when they were exposed to negative stimuli.
Several studies from this review also demonstrated decreased activation in the PFC and ACC in GAD patients during the viewing of emotional stimuli in contrast to the control groups.
One study displayed increased functional connectivity between the ACC and the amygdala after induction of perseverative cognition such as worrying and ruminative thoughts. The findings from this study revealed that enhanced activation between these brain areas was associated with worry in patients with GAD. Enhanced activation in the PFC and ACC has been associated with emotional regulation in healthy individuals. However, emotional regulation seems to malfunction in patients with GAD which can lead to problems in the interpretation of emotional and social events. Further, GAD has been associated with lower well-being and life satisfaction and may even be a risk factor for suicidal thoughts. Therefore, it is of great importance to identify the neural correlates of GAD since it may help to develop better treatments such as more effective psychotropic drugs or improved psychotherapy.
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