Understanding the link between childhood trauma and bipolar disorder

Understanding the link between

childhood trauma and bipolar disorder

A systematic review of structural neuroimaging studies

Marie Reimer

Project thesis Total credits: 20

Supervisor: Dr. Monica Aas

Research and Development, R&D. Department Vestre Viken Hospital trust, Co-supervisor: Prof Ole A Andreassen

Clinical Medicine, University of Oslo

February 2022

1. Abstract

Accumulating evidence indicates that childhood trauma (CT) is a risk factor for developing bipolar disorder (BD) but the underlying mechanism for their association is not established.

There are several original articles that study CT and magnetic resonance imaging, MRI (both whole brain and ROI approach) of the brain in BD patients, but a systematic review on the subject is missing.

The aim of this article was to perform a literature review investigating the association between CT and magnetic resonance imaging (MRI) in adult BD patients. A systematic review of existing literature on the topic was conducted. We included studies comprised of adult subjects with BD with data available for a history of CT as well as having a brain scan for measuring brain volume (sMRI). In total 10 studies were included.

The most reoccurring result was the association between BD patients with CT and decreased gray matter volume (GMV) in the brain; this was reported in six of the ten studies. Different methods were used, and different regions of the brain analyzed, but in total a significant decrease was found in hippocampus, right precentral gyrus, thalamus, prefrontal

cortex/frontal lobe, insula, and corpus callosum (CC). However, two of the studies found that CT was associated with an increase of GMV in BD patients, more specific in amygdala and hippocampus. Analyses were regulated with different confounders. CT experience was based on recall with a risk of bias, and in general the sample groups in the studies were small. It appears CT had a negative effect on the GMV in the BD group, but due to these limitations, it is too early to draw a conclusion.

Key words - Childhood trauma, MRI, Bipolar disorder

Abbreviations - BD: Bipolar disorder. CT: Childhood trauma. HC: health control. GMV:

gray matter volume. CC: Corpus Callosum. RFQ: Risky family questionnaire. CTQ:

childhood trauma questionnaire. ROI: region of interest. MRI: magnetic resonance imaging.

Table of content

1. Abstract ... 2

2. Introduction ... 4

1.1 Bipolar disorder ... 4

1.2 Childhood maltreatment and bipolar disorder ... 5

1.3 MR and bipolar disorder ... 6

1.4 Subfields of the brain ... 7

2. Methods ... 10

2.1 Search strategy ... 10

2.2 Studies identification ... 10

2.3 Inclusion criteria ... 11

2.4 MRI ... 13

2.5 Risk of bias assessment ... 13

3. Results ... 14

3.1.1 GMV reduction observed in BD patients with CT ... 14

3.1.2 GMV reduction observed in HC subject ... 16

3.2 GMV increase observed in BD patients with childhood trauma ... 17

3.3 Confounders ... 17

3.4 Childhood trauma ... 18

3.5 Limitations ... 19

4. Discussion ... 20

4.1 Method ... 20

4.2 Confounders ... 21

4.3 Limitations ... 22

4.4 Childhood trauma ... 23

4.5 Mechanisms ... 24

4.5.1 Emotional hyper-reactivity ... 24

4.5.2 Inflammation ... 24

4.5.3 Stress ... 25

4.5.4 Glutamate ... 25

5. Conclusion ... 26

6. References ... 27

7. Tables and Figures ... 31

Figure 1: Flow chart of article selection process ... 31

Table 1: A descriptive overview of the samples included in this review ... 31

Table 2: Summary of the results: associations between childhood trauma and brain alterations in bipolar disorder patients. ... 36

Table 3: Confounders ... 36

Table 4: Newcastle-Ottawa Quality Assessment ... 37

2. Introduction

Several studies have found evidence of an association between greater childhood trauma (CT) and poorer cognitive performance on patients with bipolar disorder (BD) (Dauvermann &

Donohoe, 2018). This highlights the importance of the effect of CT on BD, and in this study we will investigate how this is connected to brain image measurements. There are several original articles that study CT and MRI (both whole brain and ROI approach) of the brain in BD patients, but a systematic review on the subject is missing, and that is the scope of this study.

1.1 Bipolar disorder

BD is a mental illness that causes mood swings that range from periods with extremely “up”, energized behavior (manic episodes) to very “down”, sad periods (depressive episodes).

Simplified you can divide the illness into two types, BD I and II. Type I is characterized with manic episodes over 7 days that lead to loss of everyday function, often followed by a period of low mood (a depressive episode). BD type II is characterized by depressive episodes and hypomanic episodes. Hypomanic episodes are periods of elevated mood without reaching the threshold of being a manic episode (NIMH, 2020). BD is associated with high disability, reduced life quality, morbidity, and risk of suicide (Malt, 2021).

BD type I has a lifetime prevalence at approximately 1%, whereas BD type II is more common and is seen among 2-4% of the Norwegian population (Malt, 2021).

A typical course of the illness is a functional impairment starting as a teenager, followed with the first manic/depressive episode around the age of 21 (Kate E. A. Saunders, 2018). There are gender differences between the clinical course and features of BD (Arnold, 2003). Studies show that women have significantly later age of onset compared to men, with approximately 3.2 years later occurrence of illness. In addition, it is implicated that women experience a seasonal pattern of mood disturbances, mixed mania, depressive episodes, and rapid cycling more often than men (Arnold, 2003). The severity of the illness and number of episodes varies (Fisfalen et al., 2005). For example, having relatives with a BD diagnosis is associated with the episode frequency (Fisfalen et al., 2005), while another study suggests that

antidepressants may be associated with episodes occurring more frequently (Schneck et al., 2008). In a 40-year-follow-up study done on a Zurich cohort they found that 16% recovered, but 50% were still struggling with recurring episode (Kate E. A. Saunders, 2018).

The treatment depends on what type of BD that is being treated and varies between episodes and stable periods. It is common to combine medical treatment and psychotherapy. Lithium is a well-documented mood stabilizer medication often used to treat BD. Lithium has been recommended as a first-line treatment for maintenance therapy by all relevant guidelines, for nearly 70 years (Volkmann, Bschor, & Kohler, 2020). Studies indicate that prolonged

treatment of lithium may have a neuroprotective effect (Powell et al., 2018), with greater grey matter volume in BD treatment with lithium compared to BD patients not treated with lithium (Sun et al., 2018)

The etiology behind developing BD is complex. Studies have shown that there is an interplay between genetics and environmental factors such as stress, sleep, drugs etc., that is giving rise to the illness. Based on twin studies the genetic factors account for approximately 60-80% of the cause to developing BD (Smoller & Finn, 2003). However, a more recent study by Musliner et al., (2020) looking at the polygenic risk of developing BD among individuals diagnosed with unipolar depression at an early age (10-35 years old), showed that the risk of progression was 7,3% for BD. After they adjusted for polygenic risk scores (PRSs), the results showed that parental history strongly predicted progression to BD with a hazard ratio of 5,02 (Musliner et al., 2020). In addition, some studies have looked at risk indicators of unfavorable outcome of BD, and found that adverse childhood experiences, impulsivity and comorbid anxiety often complicate the presentation of the course of BD (Song et al., 2020).

1.2 Childhood maltreatment and bipolar disorder

Early life stress can be used as an umbrella term for several types of early stressors, such as childhood maltreatment, CT, exposure to bullying at school, parental loss or childhood adversities. World Health Organization (WHO) defines child maltreatment as follows; “child maltreatment is the abuse and neglect of people under 18 years of age. It includes all forms of physical and/or emotional ill-treatment, sexual abuse, neglect or negligent treatment or commercial or other exploitation, resulting in actual or potential harm to the child’s health, survival, development, or dignity in the context of a relationship of responsibility, trust or power. Four types of child maltreatment are generally recognized: physical abuse, sexual abuse, psychological (or emotional or mental) abuse, and neglect”(WHO, 2017).

WHO reports estimate that a quarter of all adults have been physically abused during their childhood. Sexual abuse reports show that 1 out of 5 women, and 1 out of 13 men have been sexual abused at the age 0-17 years. Exposure to CT is associated with clinical and

psychosocial impairments in adulthood, as well as being a risk factor for developing several psychiatric disorders, including BD (Aas et al., 2016). CT is reported at a higher rate among people with mental disorders (Souza-Queiroz et al., 2016; Aas et al., 2016). A review from 2016 investigating the relationship between childhood adversity and BD, showed that individuals with BD are 2,6 times more likely to have experienced CT compared to healthy controls (HC) (Palmier-Claus, Berry, Bucci, Mansell, & Varese, 2016).

Several reviews on CT and BD (Daruy-Filho, Brietzke, Lafer, & Grassi-Oliveira, 2011; Etain, Henry, Bellivier, Mathieu, & Leboyer, 2008; Aas et al., 2016), state an association between CT and the severity of the clinical expression of BD and/or the susceptibility. The reviews show that CT is associated with several clinical characteristics of BD, including earlier onset of the illness, rapid cycling course, higher number of mood episodes, increased risk of suicide attempts and substance misuse. Whereas the risk of both suicide attempts and substance misuse, is elevated by CT independent of psychiatric diagnoses/BD. They also highlight how different types of CT are more related to the specific associations. Earlier age of onset is associated with emotional abuse and neglect (Aas et al., 2016). Emotional abuse and sexual abuse are predictors for suicide attempts. Sexual and physical abuse are predictors to

substance misuse (Aas et al., 2016). In addition to greater severity, exposure to CT will also associated with more comorbidity, earlier onset age, more suicidal behavior, and less

favorable response to treatment in BD patients (Duarte et al., 2016). However, a review article on CT and MRI in BD are currently lacking in the literature.

1.3 MR and bipolar disorder

Magnetic resonance imaging (MRI) is a scan that produces detailed images of the inside of the body, using strong magnetic fields and radio waves. A recent article by Waller, Miao, Ikedionwu, & Lin, (2021) looking into MRI abnormalities in BD patients, states that multiple brain abnormalities have been established by structural neuroimaging in BD subtypes, both in grey and white matter. They hypothesize that the structural reduction seen in gray matter volume (GMV) may be associated with functional deficits. The article refers to different studies that have found GMV reduction in bilateral inferior and left superior frontal gyrus (Tang et al., 2020), lateral orbitofrontal cortex (Nugent et al., 2006) and hippocampus (Ott, Johnson, Macoveanu, & Miskowiak, 2019). In a multicenter study (Hibar et al., 2018) thinner cortical grey matter was observed in parietal, temporal and frontal regions in both

hemispheres. In the same study BD was also correlated with reduced thickness and surface

area in the supramarginal gyrus and insula. Another study Koshiyama et al., (2020) observed reduced fractional anisotropy in the cingulate gyrus in addition to white matter alterations in the fornix and corpus callosum. White matter reduction was also recorded in the corticospinal tract and the superior longitudinal fasiculus (Tang et al., 2020). For amygdala the review suggests that the changes in functional and structural connectivity are age-specific (Waller et al., 2021). For adults they have observed both an increase and decrease in amygdala volumes.

However, when investigation BD youth they found decreased amygdala volumes (Waller et al., 2021). The review article by Waller and colleagues states that these findings demonstrate MRIs potential to become a clinically component in the process of diagnosing and following up BD patients. However, they point out that more consistent rates of classification accuracy are necessary to be able to distinguish between BD subtypes and psychiatric disorders (Waller et al., 2021).

In a longitudinal study from 2021 where 1232 individuals underwent brain MRI scans at two time points, Abe and collages investigated structural brain changes in BD compared to healthy controls (HC) and a yearly change rate in brain structure using structural MRI was calculated. The results showed that HC subjects had lower cortical thickness change rates, but in surface area regions of interests (ROIs), they showed both higher and lower change rates compared to BD. BD patients showed a faster enlargement of ventricular volumes and a slower thinning av fusiform and parahippocampal cortex. They also found an association between (hypo)manic episodes and faster cortical thinning (Abe et al., 2021).

1.4 Subfields of the brain

CT in adults with mental illness amount to negative outcome in several aspects, including morphology changes in the brain. Areas affected are particularly amygdala, hippocampus, prefrontal cortex and corpus callosum (Aas et al., 2016; Janiri et al., 2017).

Gray matter in the brain is a major part of the central nervous system and consists mainly of neuronal cell bodies. Deep gray matter structures construct neural circuitry underlying emotion regulation and processing (Janiri et al., 2017). A study from 2014 recognized gray matter structures as fundamental areas involved in BD mechanisms (Phillips & Swartz, 2014).

The frontal lobe is indicated to be involved in higher-order cognition and top-down regulation of motivation processing, affect and social-emotional behavior. The development of the

frontal lobe is relatively slow, this makes the region vulnerable to negative influences longer than other regions with rapid maturation. Not until the brain is fully developed in late

adolescence or early adulthood, will the potential suboptimal functioning become apparent, this is when BD is typically diagnosed (M. J. H. Begemann et al., 2021).

Amygdala and hippocampus are part of the same neural network accountable for the stress response and emotional processing. Hippocampus inhibits ventromedial prefrontal cortex (vmPFC), this releases amygdala from its own inhibition. Studies report functional

abnormalities connectivity in the limbic system among BD patients, leading to alterations in emotional processing and regulation. A potential reasoning for limbic functional

abnormalities is adjustments in limbic structures volume and reduces white matter integrity in tracts connecting them (Souza-Queiroz et al., 2016).

Hippocampus is an important brain area involved in the regulation of the stress response, emotional response to trauma and the processing of traumatic memories (Janiri et al., 2019).

A meta-analysis from 2017 showed an inverse correlation between childhood adversity in a non-clinical population and hippocampal volumes. Smaller hippocampus volumes are also associated with BD (Calem, Bromis, McGuire, Morgan, & Kempton, 2017). A large study from 2016 with 1710 BD patients and 2594 health controls (HC) found a consistent

volumetric reduction of mean hippocampus in BD patients (Hibar et al., 2016). Amygdala is also a brain area considered an important mediator for biological responses to stress.

Additionally, it is involved in mechanism for learning, memory and social behavior (Holck, 2020).

A study published in 2011 found an association between BD, lithium, and structural brain changes. The patients treated with lithium displayed increased hippocampal and amygdala volume compared to HC and BD subjects not treated with lithium. This study also stated a reduction in cerebral volume in BD patients compared to HC, additionally they found an association with the reduction and the duration of the illness in individuals (Hallahan et al., 2011).

Corpus callosum (CC) has an important role in mediating communication between the left and right cerebral hemisphere, in addition to coordinating cognitive processes as attention, emotion, arousal, and higher cognitive abilities (Bucker et al., 2014). Greater CC volume is

associated with increased cognitive capability and higher myelination is associated with greater cognitive capacity in the teens. CC is particularly vulnerable to stress and trauma in the childhood, due to the slow development. The development process is completed in early adult life, the process of myelination goes on during childhood and early adolescence.

Different regions of the CC develop and reorganize during different time periods during the brain development. Leading us to assume that the CC might have different intervals of vulnerability to early traumatic experiences. This can potentially lead to reduction of the CC volume and corruption in the communication between the cerebral hemispheres, and result in cognitive weakening in distinct areas, for instance attention, arousal, language and memory (Bucker et al., 2014). Structural abnormalities in the form of decreased anterior and posterior regions of CC (Rinne-Albers, van der Wee, Lamers-Winkelman, & Vermeiren, 2013) and delayed myelination of the CC has been associated with CT (Kaplow & Widom, 2007).

Based on the association between childhood trauma and brain abnormalities and the vast majority of studies showing childhood trauma as a risk factor in BD, we examined the current brain volume imaging studies to broaden the knowledge on this link. Therefore, a systematic review of brain volume alterations in BD was conducted to determine if brain volume abnormalities in BD are related to CT experiences in BD?

Here we systematically review the existing literature on the topic of childhood trauma and structural MRI in adult subjects with BD.

2. Methods

2.1 Search strategy

The main electronic search was conducted on MEDLINE and PsycINFO via Ovid provider as well as Cochrane Libraries, up to December 2021. The keywords used where: “bipolar

disorder” AND “MRI” or ”Brain volume” AND “childhood trauma”. We then continued to complete the search manually. No additional original articles were identified using the biography of the selected papers, or via “related articles” function of PubMed Medline and via google scholar. Titles and abstracts, and subsequently selected eligible full texts of articles were screened independently by 2 reviewers (M.R. and M.A.). Discrepancies in titles

included were resolved in a project meeting. As a result of this search, we retrieved 33

articles, whether we used “MRI” or “brain volume” as keyword did not change the number of articles included in the review.

2.2 Studies identification

To identify relevant studies, we used PRISMA recommendations. During the first step in sorting the articles we screened the titles and abstracts to identify if the studies were relevant based on our criteria. Two researchers (MR and MA) independently screened through all the articles. After the first screening MR picked out 18 articles, and MA picked out 15 articles combining a total 21 articles. The two researchers (MR and MA) then read the full text and discussed in project meetings the 21 articles chosen. 11 articles where now excluded; 8 articles because of the absence of analyses in the group of BD subjects, the last 3 because the articles didn´t look into MRI volumes. 10 articles were included in the systematic review.

There were no articles on the subject published before 2012 in our search, the articles we included were published between 2014-2021. The identification, selection and inclusion process are detailed in Figure 1.

To control the quality of the articles used in the review the two researchers (MR and MA) performed a quality assessment on all the articles used in a project meeting. The Newcastle- Ottawa Quality Assessment form for cohort studies was applied. The Newcastle-Ottawa Scale (NOS) is a collaboration between the University of Newcastle, Austria and Ottawa, Canada. It consists of a “star system” where a study is evaluated on three vast perspectives: the selection, comparability, and outcome of the study. The “star score” is then converted to AHRQ

standard of either good, fair, or poor quality, based on the number of stars the study gets in

each section. See Table 3 for an elaborate description of threshold for good, fair, and poor quality standards.

2.3 Inclusion criteria

The main inclusion criteria to be included in the review was to be a structural MRI study in BDs and data on a history of childhood trauma/maltreatment had to be presented. The MRI scans of the brain should be looking at GMV either whole brain or region of interest (ROI).

Nine of the articles studied in this review used DSM-IV/DSM-V to diagnose their subjects with BD (M. J. H. Begemann et al., 2021; Bucker et al., 2014; Duarte et al., 2016; Janiri et al., 2019; Janiri et al., 2017; Poletti et al., 2014; Poletti et al., 2016; Song et al., 2020; Souza- Queiroz et al., 2016), while one study (Quide et al., 2021) used ICD-10 criteria to diagnose the individuals with BD.

Diagnostic and Statistical Manual of Mental Disorders, DSM, is an American classification system for psychiatric disorders published by the American Psychiatric Association (ASA).

DSM was published for the first time in 1952 as an American version on the international classification of diseases and related health problems (ICD-10). The newest version is DSM- V that was published in 2013, the biggest changes form DSM-IV is that they stopped using the multiaxial diagnosis system, the diagnostic criteria for certain diagnosis were changed, and the separation between adult- and child- & teenager-psychiatric diagnosis were removed.

The DSM-system is the most used classification system in psychiatric research (Malt, 2020).

International classification of diseases and related health problems, ICD, is the international statistical classification system for diseases and related health problems. The world health organization (WHO) is responsible for updating and maintaining the ICD, in 1992 they updated it to ICD-10, and in 2019 to ICD-11, with approval to implement it as of 2022. ICD- 11 is more closely related to DMS-V than DSM-IV was to ICD-10 (Braut, 2022; Malt, 2022).

Eight studies evaluated CT using the Childhood Trauma Questionnaire (CTQ) (M. J. H.

Begemann et al., 2021; Bucker et al., 2014; Duarte et al., 2016; Janiri et al., 2019; Janiri et al., 2017; Quide et al., 2021; Song et al., 2020; Souza-Queiroz et al., 2016), and two of the studies used the Risky Families Questionnaire (RFQ) (Poletti et al., 2014; Poletti et al., 2016). In Poletti et al., (2014) and in Poletti et al., (2016) they divided the patient group into two groups

based on the median score on the RFQ. In M. J. H. Begemann et al., (2021), Janiri et al., (2019) and in Janiri et al., (2017) a cut of score for each type of trauma was used to relent four levels of CT: none, low, moderate, and severe. The participants were considered to have a history of CT if one or more subscales met the cut-off criteria for moderate or severe trauma.

While in Bucker et al., (2014), Duarte et al., (2016), Quide et al., (2021), Song et al., (2020) and Souza-Queiroz et al., (2016) they used the total CTQ score to represent the severeness of CT.

In the CTQ participants answer questions that estimate the frequency of traumatic experiences during childhood, defined as maltreatment occurring before the age of 18. CTQ screens for five types of trauma: emotional abuse (5 questions), emotional neglect (5 questions), physical abuse (5 questions), physical neglect (5 questions) and sexual abuse (5 questions). The questions related to trauma are answered on a five point rated scale, ranging from 1 (never true) to 5 (very often true). You end up with a summery score ranging from 25-125 and a score for each trauma subtype from 5-25. The higher the score, the higher the severity of the CT. Cut off scores divides each type of trauma in to four levels of maltreatment: none, low, moderate, and severe. The eight mentioned studies using the CTQ, used the short form. This is a self-reported questionnaire consisting of 28 questions, 25 questions covering the five different types of trauma as listed above, in addition to 3 questions included to detect subject that are underreporting traumatic experiences. The reliability of the CTQ has been tested and verified with BD patients (Etain et al., 2010).

Risky Families Questionnaire was originally created by (Felitti et al., 1998) to determine the relation of family stress to physical and mental health outcomes in adulthood. The

questionnaire rates the degree of harsh parenting with obvious conflict in the family, and inadequate nurturing of the child experiences in the household. The questionnaire studies seven categories of adverse childhood experiences in total; Three categories for childhood abuse: physical ( 2 questions), psychological (2 questions) and sexual abuse (4 questions); and four categories covering the exposure to home environment dysfunction during childhood:

exposure to mental illness (2 questions), substance abuse (2 questions), violent treatment of mother or stepmother (4 questions) and criminal behavior (1 question). If the patient

responded with “yes” to one or more of the questions in the category they were defined as exposed to the category (Felitti et al., 1998).

2.4 MRI

When it comes to MRI imaging and method used in this area, most of the studies had the same approach. All studies used a 3T MRI scanner, apart from Duarte et al., (2016), who used a 1,5T MRI scanner.

The software packages applied to analyze and visualize the data were Freesurfer and Statistical parametric Mapping (SPM). Freesurfer was used in four of the studies (M. J. H.

Begemann et al., 2021; Bucker et al., 2014; Janiri et al., 2019; Janiri et al., 2017), while SPM was used in the other six studies, both the old version SPM8 (Duarte et al., 2016; Poletti et al., 2014; Poletti et al., 2016; Souza-Queiroz et al., 2016) and the new version SPM12 (Quide et al., 2021; Song et al., 2020) was used. Freesurfer is a processing stream for MR imaging data used to visualize and analyze functional, structural and diffusion neuroimaging data from longitudinal and cross-sectional studies. Among other things it includes skull-stripping, registration, bias field correction, diffusion tractography toolboxes, and anatomical segmentation, in addition to cortical surface reconstruction, parcellation and registration (Doug Greve, 2021). The SPM software package is designed to analyze brain imaging data sequences, that can be time-series from the same subject, or sequences of images from various cohorts. The SPM8 software was updated to SPM12 in 2014 (Guillaume Flandin, 2008).

2.5 Risk of bias assessment

For each study included in our review, we assessed the following risk of bias reported in Table 1:

- Participants: number of subjects included. The presence of a control group.

- Information about CT assessment. The use of a validated instrument. Use of validated cutoff scores when separating into participants with and without CT.

- The quality of the imaging method (normalization, visual inspection of the images).

- Adjustments in the analyses (age, sex, medication, intracranial volume (ICV) etc).

Statistical thresholds. Corrections of multiple comparisons.

3. Results

After screening title, abstract and full-text we ended up with 10 studies exploring the associations between CT and brain alterations in BD, see Table 1. The articles focused on different brain areas in their studies, some had a whole brain approach without focusing on established areas, while others had hypothesis driven region of interest (ROI) approach.

Looking at all the studies in total, the BD patients participating, including both participants with and without a history for CT, had a mean age of 43,25 years old, and 57,23% were female. The HCs had a mean age at 39,53 and 54,5% were female.

A summary of the main findings is reported in Table 2. In six of the studies (M. J. H.

Begemann et al., 2021; Bucker et al., 2014; Duarte et al., 2016; Poletti et al., 2014; Poletti et al., 2016; Song et al., 2020) we observed a reduction in GMV in brain structures in BD

patients with a history of CT. However, the reduction was observed in different brain areas. In Song et al., (2020) a reduction in GMV was observed in right precentral gyrus, while Bucker et al., (2014) found a reduction in corpus callosum (CC) volumes. Poletti et al., (2014) reported an association between CT and a reduction in hippocampus, whilst Duarte et al., (2016) observed a reduction in the right dorsolateral PFC and the right thalamus. Finally, Begemann et al., (2021) observed a reduction in the frontal lobe of BD patients with CT, and Poletti et al., (2016) in prefrontal cortex, insula and thalamus. In Quide et al., (2021) and in Souza-Queiroz et al., (2016) a decrease in GMV associated with CT was observed in the HC subjects, but not in BD patients, located in amygdala, bilateral precuneus, inferior/superior parietal lobule and postcentral gyrus. A contrasting result was observed in Janiri et al., (2019) and in Janiri et al., (2017), with an increased in GMV respectively in hippocampal subfields and in hippocampus and amygdala, in BD with CT compared to BD without CT.

3.1.1 GMV reduction observed in BD patients with CT

In Song et al., (2020) a reduction in GMV was found in multiple cortical and subcortical areas in BD compared to HC, more specifically in: bilateral hippocampus, bilateral precentral gyrus, left temporal gyrus, right fusiform gyrus, left thalamus, right insular lobe and left middle frontal gyrus. No brain regions had a significantly increased GMV in BD patients compared to HC. In addition, investigating the history of CT, Song and colleagues found that patients with BD with a history of CT had a significantly smaller volume of the GMV in the right precentral gyrus, and a trend towards smaller GMV in the left middle frontal gyrus.

Moreover, the study found that a history of CT correlated with symptoms of impulsivity from

the Barratt Impulsiveness Scale (BIS) and anxiety from Beck Anxiety Inventory (BAI). Both CT and symptoms (impulsivity and anxiety) loaded on the same brain regions. More specific there was a negative correlation between GMV in the right precentral gyrus and BIS score, and GMV in the left middle frontal gyrus and BAI scores.

Bucker et al., (2014) reported a reduction in corpus callosum (CC) volumes in BD patients with a history of CT. More specifically there was a significantly smaller volume in the

anterior region of CC in BD patients with CT compared to BD patients without CT, but not in the HC independent of CT. There was no significant difference in the central and posterior region of CC. Looking at different types of childhood abuse, they found a significant

difference in BD patients with emotional- and sexual abuse compared to BD patients without respectively emotional- and sexual abuse. Patients with emotional abuse had a significant reduction of the posterior and total volume of CC compared to patients without emotional abuse. Patients with sexual abuse had a significant reduction in volume of the central region of CC compared to patients without sexual abuse. There was no significant difference for physical abuse, emotional neglect, or physical neglect.

The goal of the study Poletti et al., (2014) was to test the hypothesis that factors influencing the glutamate clearance could interact with the rate of stress exposure in mediating the stress effect on hippocampus, by studying the effect of SLC1A2-181A > C polymorphism and history of CT on hippocampal GMV of patients with BD. They observed a reduction in hippocampus GMV. Patients exposed to higher levels of adverse childhood experience had a smaller GMV in two main clusters in the right, and one cluster in the left hippocampus.

SLC1A2–181A > C only had an effect among patients exposed to lower levels of CT. T/T and G/G homozygotes respectively showed the lowest and highest levels of GMV in one main cluster in left hippocampus and two in right hippocampus. With patients exposed to high levels of CT, all genotypes showed related lower GMV.

In Duarte et al., (2016) a trend towards reduced GMV in right dorsolateral prefrontal cortex was identified among BD-I patients with childhood maltreatment (CM) compared to HC.

When looking at the CTQ total score and all the CT subtypes as separate continuous variables in a whole brain analysis, no significant association in GMV was found. However, when using a small volume correction (SVC) approach in a hypothesis driven ROI analysis, a

significant negative correlation was found between CTQ total score and right dorsolateral prefrontal cortex GMV and right thalamus.

Begemann et al., (2021) reported that in the total sample (both BD and HC) a history of CT was associated with GMV reduction in the frontal lobe, not in other (sub) cortical lobes. The regions within the frontal lobe that were affected were: right medial orbitofrontal, paracentral, superior frontal and left precentral region. The correlation was independent of trauma

subtype. The results also showed that the total cerebral brain volume was significantly reduced in BD patients compared to HC, and that mean CTQ score was higher for BD

patients compared to HC. CT severity was not associated with GMV changes in hippocampus or amygdala.

In Poletti et al., (2016) they found a significant difference in regional GMV between BD patients and HC. BD patients had a significantly lower GMV compared to HC in the right orbitofrontal cortex (OFC). Considering the effect of high levels of CT, they found a significant GMV reduction in BD patients compared to HC in bilateral OFC, insula and thalamus. No significant differences were observed in groups with subjects with low levels of CT.

3.1.2 GMV reduction observed in HC subject

Two studies observed a reduction in GMV concentration in HC with CT (Quide et al., 2021;

Souza-Queiroz et al., 2016), but no significant regression in GMV in brain structures in BD patients, independent of history of CT, was found. The study (Quide et al., 2021) had a hypothesis that both systemic inflammation and CT severity would be negatively associated with changes in brain networks that involve stress-sensitive regions regardless of diagnostic status. Additionally, they expected the severity of CT exposure to modify the relationship between brain morphology and systemic inflammation, dependently of diagnostic status. They observed an association between increased inflammation in HC exposed to high levels of CT and decreased positive voxel (bilateral PPC/precuneus, inferior/superior parietal lobule, postcentral gyrus) and increased negative voxel (left middle temporal gyrus). No significant association was found between systemic inflammation and GMV in BD patients, independent of CT levels. The study by Souza-Queiroz et al., (2016) looking at the limbic network

specifically, found a reduction in amygdala volumes related to CT (total CTQ score) in HC

subjects. No significant regression was found in hippocampus or amygdala in BD patients with and without CT.

3.2 GMV increase observed in BD patients with childhood trauma

In Janiri et al., (2019) and Janiri et al., (2017) the results differed from this general finding with a reduction in GMV in brain structures in BD patients with CT. They observed an increase in GMV in BD patients with CT compared to HC, in the hippocampal subfields (CA1, presubiculum and subiculum volumes (Janiri et al., 2017)), as well as the larger hippocampus and amygdala (Janiri et al., 2017). Notably the two studies reported data from det same population, the study sample from (Janiri et al., 2019) overlapped 85% with the earlier study on the same subject (Janiri et al., 2017), whereas one BD patient and 32 HC were excluded in the second study (Janiri et al., 2019) because of errors in the hippocampal

subfields segmentation. In HC exposed to CT they found an association with decreased total hippocampal volumes.

3.3 Confounders

The different studies used various covariates in the analyses. The most common covariates were sex and age. The covariates are listed in Table 3.

The effect of treatment, more particularly the effect of lithium, was included as a covariant in five of the ten studies (M. J. H. Begemann et al., 2021; Janiri et al., 2019; Poletti et al., 2016;

Souza-Queiroz et al., 2016). While in one of the studies (Poletti et al., 2014) none of the patients took lithium within the last 6 months before the scan. In Bucker et al., (2014), Duarte et al., (2016), Janiri et al., (2017), Song et al., (2020) and Quide et al., (2021), they recorded the lithium treatment usage but did not add it as a covariant in their analysis.

Intercranial volume was another covariant adjusted for in seven of the ten studies. Studies that did control for ICV were Bucker et al., (2014), Janiri et al., (2017), Janiri et al., (2019), Poletti et al., (2016), Song et al., (2020), Souza-Queiroz et al., (2016) and Quide et al., (2021). In Poletti et al., (2016) they found a significant reduction in ICV in BD patients compared to HC. In Janiri et al., (2019) they observed a bilateral significant effect of diagnosis on all the ICV-corrected hippocampal subfield volumes. In Bucker et al., (2014) they observed a non- significant trend suggesting a difference in the ICV between patients without trauma, patients

with trauma and HC. In Souza-Queiroz et al., (2016) the results showed that BD patients among other things, did not differ significantly from HC considering total ICV.

3.4 Childhood trauma

All the studies had a subject group of BD patients with a history of CT, but it differed whether the HC subjects had a history of CT. The most common participant set up was HC subjects with a history of CT, were the CT severity was reported as lower than the BD patients (M. J.

H. Begemann et al., 2021; Janiri et al., 2019; Janiri et al., 2017; Poletti et al., 2016; Quide et al., 2021; Souza-Queiroz et al., 2016). Some of these studies had two separate HC groups in their analysis, one with and one without CT (M. J. H. Begemann et al., 2021; Janiri et al., 2019; Janiri et al., 2017). In three of the studies no HC subjects had a history of CT (Bucker et al., 2014; Duarte et al., 2016; Song et al., 2020). In one of the studies (Poletti et al., 2014), there were no HC participating. In general, all the studies reported a higher coincidence of CT among BD patients compared to HC.

Some of the studies considered a history of CT as the presence of any type of CT, only considering the total CTQ score (Janiri et al., 2017; Song et al., 2020) or total RFQ score (Poletti et al., 2014; Poletti et al., 2016). Whereas some of the studies looked at both the total score of CTQ and divided their results into subgroups of CT based on the CTQ score of physical neglect, physical abuse, emotional neglect, emotional abuse, and sexual abuse (M. J.

H. Begemann et al., 2021; Bucker et al., 2014; Duarte et al., 2016; Janiri et al., 2019; Quide et al., 2021; Souza-Queiroz et al., 2016).

The prevalence of the different types of CT differed. In Quide et al., (2021) the BD patients reported a greater level of sexual abuse, emotional abuse and total CTQ score compared to HC. The level of exposure to physical abuse did not differ among the two groups.

In Bucker et al., (2014) they found a significant differences in the CC volume for specific subtypes of trauma. The posterior, anterior and total volume of CC was significantly decreased in BD patients with a history of emotional abuse compared to those without. For sexual abuse there was a significant reduction in the central region of CC compared to BD patients without sexual abuse. There were no significant differences observed for physical abuse, emotional neglect, or physical neglect. When they did a CT subtype analyses in (Duarte et al., 2016), with age, gender, and parental education as covariates, they found a negative correlation between CTQ physical neglect score and right thalamus GMV, CTQ

physical abuse score and right dorsolateral prefrontal cortex GMV, and CTQ emotional neglect score and right thalamus GMV.

Begemann and colleagues reported a dose relationship between amount of CT and GMV reduction. When they looked at the whole sample in Begemann et al., (2021), they observed more pronounced frontal GMV reductions in subjects reporting a higher number of CT subtypes. Indicating a dose-response pattern with higher severity of overall trauma rated, independent from the subtype of trauma, is associated with pronounced GMV reduction in the frontal lobe. Significant dose-response patterns were observed in both BD-I patients and HC.

3.5 Limitations

In general, the sample size in the studies was somewhat small. It varied from the smallest BD subject group in Souza-Queiroz et al., (2016) with 32 participants, too 250 BD subject in (M.

J. H. Begemann et al., 2021) making this the study with the largest BD sample group. Number of BD subjects and HC controls for the different studies are listed in Table 1 as well as a limitation, risk of bias section.

In the Newcastle-Ottawa quality assessment the studies got a total score of either 4 or 5 (see Table 4). Seven of the studies got a total score of 5 (M. J. H. Begemann et al., 2021; Bucker et al., 2014; Janiri et al., 2019; Poletti et al., 2016; Quide et al., 2021; Song et al., 2020; Souza- Queiroz et al., 2016) with respectively 2, 2 and 1 star in the Selection, Comparability and Outcome domain. Duarte et al., (2016) and Janiri et al., (2017) got a total score of 4 points with respectively 2, 1 and 1 stars. Poletti et al., (2014) also had a total score of 4 with a score of 1, 2 and 1 star, respectively. The results are listed in Table 3. Scores suggest low to fair quality of the studies.

4. Discussion

Since the first study in 2014, the association between a history of CT and structural brain alterations in adults with BD have been investigated in at least 10 papers. Imaging studies were conducted using 3T scanner (nine studies) or 1,5T scanner (one study) with automated obtained whole brain and regions of interest using Freesurfer version 5.3 (three studies) or 5.1 (one study), or SPM version 8 (four studies) or 12 (two studies).

The most reproduced results were a negative relation between a history of CT and reduction of gray matter in BD (see Table 1). Two studies by (Janiri et al., 2019; Janiri et al., 2017) reported a positive association between CT and larger amygdala and hippocampal volumes in BD. Two studies found a negative association between CT and GMV in HC but not in BD (Quide et al., 2021; Souza-Queiroz et al., 2016).

4.1 Method

The ten studies included in this analysis have employed different methodologies to

characterize the effect of CT on the brain. Some have focused on specific regions of interest (ROI) (Bucker et al., 2014; Janiri et al., 2019; Janiri et al., 2017), while others have done whole-brain analyses (Poletti et al., 2014; Poletti et al., 2016; Quide et al., 2021). Lastly, in Begemann et al., (2021, Duarte et al., (2016), Song et al., (2020), and Souza-Queiroz et al., (2016) they did both a whole brain and a ROI analysis.

The studies that did a ROI analysis, did a hypothesis-driven investigations of selected ROI where abnormalities have been previously identified in MRI studies of CT or BD. The ROI differed between the studies. In Souza-Queiroz et al., (2016) they analyzed the limbic system, whereas Janiri et al., (2019) focused on Hippocampus. Janiri et al., (2017) analyzed the deep gray matter volumes in caudate, putamen, pallidum, accumbens amygdala, hippocampus and thalamus, and in Begemann et al., (2021) they had hippocampus and amygdala as their ROI.

Duarte et al., (2016) did a ROI analysis on prefrontal cortex, amygdala, hippocampus, and thalamus, finally Bucker et al., (2014) had corpus callosum as their ROI. A benefit with the ROI approach is that it allows investigation of gray matter in a given set of subjects without the strict significance threshold as required for voxel-based morphometry (VBM) (Quide et al., 2021).

Choice of method for the analysis is a factor that might play a role when considering the results. For instance, in the voxel-based morphometric study from 2016 Duarte et al., (2016), they found no significant findings during their first analysis when they did a whole-brain comparison of GMV between BD-I patients and HC. However, when they did the small volume correction (SVC) approach for specific brain regions they identified a trend towards reduced GMV in BD-I patients with CT as compared to HC, in the right dorsolateral

prefrontal cortex. Equivalent results were seen in the (M. J. H. Begemann et al., 2021) study.

When interpreting the results observed in analyses with a ROI method, we need to have this in mind as the approach (Whole brain versus ROI) may affect the results based on differences in threshold for correction of multiple testing (stricter approached for whole brain than ROI), and secondly, ROI may miss important information excluding areas that may be of

importance.

4.2 Confounders

The different studies used various covariates in the analyses. In general sex and age were covariates the studies controlled for. But some studies had additional cofounders and these differed. Confounders are listed in Table 3.

Lithium was used as a covariant in the analysis in Begemann et al., (2021), Janiri et al., (2019), Poletti et al., (2016) and Souza-Queiroz et al., (2016). In the studies who did not use lithium as a covariant but who recorded the usage, it differed whether the patients

participating had similar medication profiles (Bucker et al., 2014; Duarte et al., 2016; Song et al., 2020), or if the medication profiles differed significantly (Janiri et al., 2017; Quide et al., 2021). The fact that they did not enter lithium as a covariant in their analysis, may have effect their results and should be considered a limitation. Additionally, we can speculate around if the results could be influenced greater in the studies where the treatment differed significantly within the patient group. In Souza-Queiroz et al., (2016) 89% of the patients used lithium at their main medical treatment. The results in the study reported that number of weeks under lithium treatment did not alter the results, however they speculate that the absence of results on hippocampus may be due to confounding effect of lithium treatment. ANOVAs analysis in (Janiri et al., 2019) found no significant interaction between CT and medication on

hippocampal subfield volumes. When adding lifetime history of lithium treatment as a covariant in Poletti et al., (2014), the observed data did not change. The fact that no

significant interaction between the results and lithium treatment was observed in either Janiri

et al., (2019) or Poletti et al., (2014) might indicates that adding lithium as a covariant in the analysis did not alter the results significantly. However, as we know that lithium may have a neuroprotective effect and is associated with larger GMV in BD (Sun et al., 2018), it is anyway important to include lithium as a confounder in these types of studies.

ICV was a covariant in seven (Bucker et al., 2014; Janiri et al., 2017; Janiri et al., 2019;

Poletti et al., 2016; Song et al., 2020; Souza-Queiroz et al., 2016; Quide et al., 2019) of the ten studies. The data observed on how the ICV effected the results were overlapping. In Poletti et al., (2016) and Janiri et al., (2019) they found a significant difference in ICV between BD patients and HC, and in Bucker et al., (2014) they observed a similar non- significant trend between both BT with CT, BD without CT, and HC. However, in Souza- Queiroz et al., (2016) the BD patients did not differ significantly from HC regarding the ICV.

The fact that a difference was observed in three of the studies (Bucker et al., (2014); Janiri et al., (2019); Poletti et al., (2016) underlines the importance of adding this as a covariant.

Therefor the fact that three (Begemann et al., 2021; Duarte et al., 2016; Poletti et al., 2014) of the ten studies did not calculate for this factor should be considered a limitation, however the results were overlapping.

4.3 Limitations

In addition to the variation in confounders in the studies as mentioned above, there were other components that must be considered a limitation of this review. The generally small sample size found in the ten studies used in this review is a limitation, and a larger study is necessary to validate the results found. Eight of the studies used CTQ to evaluate the exposure to CT, whereas two studies used RFQ. Both questionnaires have a risk of recall bias, considering it is a self-reporting test, taken years after the traumatic exposure. In addition, CTQ does not take the timing of the stressor, the age of onset or the duration of maltreatment into account. Even though some of the studies showed overlapping results, conflicting results were also found.

As mentioned, 8 studies found a reduction in GMV in association with CT, six of the studies found this result in BD patients compared to HC, whereas two of the studies observed a reduction in the HC subjects. Whereas two studies found an increase in GMV associated with CT in BD patients. This reduces the credibility of the results found and must be considered when evaluating the results. In Poletti et al., (2014) there were no HC subjects, this must be considered a limitation in the study. Number of participants and limitations in the different studies are listed in Table 1.

In the Newcastle-Ottawa quality assessment the studies got a total score of either 4 or 5.

Seven of the studies got a total score of 5 (M. J. H. Begemann et al., 2021; Bucker et al., 2014; Janiri et al., 2019; Poletti et al., 2016; Quide et al., 2021; Song et al., 2020; Souza- Queiroz et al., 2016) and (Duarte et al., 2016; Janiri et al., 2017; Poletti et al., 2014) got a total score of 4 points. Considering the threshold for converting the Newcastle-Ottawa scale to Agency for Health Research and Quality (AHRQ) standards the articles scored a fair-poor quality. (Poletti et al., 2014) only made the threshold for poor quality. The other nine articles reached the threshold for fair quality in the domain for selection and comparability domain, but in addition they had to score 2 or 3 stars in the outcome/exposure domain, here they only score 1 star. The studies cut short on this domain since there were no follow-ups on sample groups in the studies. Considering the purpose of the studies a follow-up of the patients does not seem that relevant, therefor this assessment form may not be that adequate in this context.

4.4 Childhood trauma

In both Bucker et al., (2014) and Duarte et al., (2016) they found a subtype specific volume reduction in respectively CC associated with emotional and sexual abuse, and right thalamus associated with physical and emotional neglect. In addition, a reduction in right dorsolateral prefrontal cortex were associated with experiences of physical abuse. The fact that the volume reduction was dependent on the subtype of trauma may indicate that the impact on brain volume might be different for different types of CT. However, when discussing this, we must take into consideration that only a small amount of the studies investigated subtypes of trauma specifically, therefor more studies, ideally with larger samples are be necessary to draw a conclusion.

As listed in the results generally all the studies reported a higher exposureof CT among BD patients compared to HC. This may be connected to the results showing a reduction in GMV in these BD patients compared to HC, indicating that CT is a factor involved in the reduction seen. We can speculate that the reason for the reduction in GMV observed is due to a higher prevalence of CT among BT patients. But a conclusion cannot be drawn, as the results are conflicting and the data samples too small.

In Bucker et al., (2014) the reduction observed in CC is only significant for BD patients with CT when compared to BD patients without CT, not compared to HC. A possible explanation

for this may be that the group sample in the study was in an early stage of their illness, recovering from their first episode of mania, meaning that the reduction in CC volume may occur later in the course of BD. This might mean that there are two sources to the reduction in CC volume in this sample group. First a reduction due to trauma, secondly a further reduction due to the illness.

4.5 Mechanisms

Several statements were suggested as possible reasons for the change in GMV observed in BD patients in specific brain regions as stated in the results.

4.5.1 Emotional hyper-reactivity

In Janiri et al., (2019) the results were conflicting compared to the results found in most of the other articles in this review. Emotional hyper-reactivity is a lability associated with CT among BT individuals (Aas et al., 2016). In Janiri et al., (2019) they suggest a possible explanation for their findings that the combination of CT and BD may aggravate the emotional hyper- reactivity in BD which may create alterations in the limbic structures, leading to increased hippocampal volumes. In addition, they point out that the ventral tegmental area (VTA) which is an essential component of reward and emotion processing, is regulated by the

hippocampus. The magnitude of the neuron response the VTA fires depends on the magnitude of the emotional response, therefor the hypersensitivity to emotional stimuli among BD patients with CT, mirrors the increased activation of VTA, which is modified by the hippocampus.

4.5.2 Inflammation

Accumulating evidence suggests that CT may be modulating the association between increased levels of inflammatory markers (such as interleukin 6, TNF-a, CRP) and brain morphology in patients with psychosis, likely trans-diagnostic. Previous studies have found increased levels of proinflammatory markers in both BD and schizophrenia patients,

compared to HC. The release of proinflammatory markers regulated the immune system by activating the hypothalamic pituitary-adrenal axis. In a study with both BD patients and schizophrenia patients increased levels of CRP were associated with being exposed to a larger number of CT types (Aas et al., 2017). In Quide et al., (2021) they found no significant association between GMV changes and systemic inflammation in BD patients, independently of their history of CT. However, in the HC group exposed to high levels of trauma an

association was found between increased inflammation and higher GMV in the left middle temporal gyris and decreased GMV in the orecuneus. This indicates that the association between GMV changes and increased systemic inflammation may depend on the level of exposure to CT.

4.5.3 Stress

The frontal lobe is generally involved in the regulation of motivational processing, affect, higher-order cognition, and social-emotional behavior. Structural brain alterations may be mediated by the trauma-related cognitive and affective deficits (M. J. H. Begemann et al., 2021). A link between CT and affective problems and cognitive deficits has been observed in patient samples and HC in several other studies (Barzilay et al., 2019; Gould et al., 2012;

McCrory, De Brito, & Viding, 2011; Pechtel & Pizzagalli, 2011). Another study by the same research group reported that more severe trauma is associated with increased adaptive stress reactivity (M. J. H. Begemann, Stotijn, Schutte, Heringa, & Sommer, 2017), decreased inhibitory control (M. J. Begemann, Daalman, Heringa, Schutte, & Sommer, 2016) and increased neuroticism levels (So, Begemann, Gong, & Sommer, 2016). A history of childhood trauma may lead to long lasting changes in the Hypothalamic-Pituitary-Adrenal (HPA) Axis as shown by higher cortisol levels in adults with childhood trauma experiences (Heim et al., 2018; Aas et al., 2019). Prolonged high levels of cortisol as a marker of

hyperactivity of the HPA axis (the biological stress axis) over time have been associated with neuronal damage (Selye, 1975) which may be a plausible link between CT and grey matter reduction in BD deserving further attention.

4.5.4 Glutamate

Exposure to stress increases the release of glutamate from hippocampus. Glutamate is an important neurotransmitter in the central nervous system, with cerebral cortex and the limbic regions of the brain containing most of the glutamatergic neurons. Increased levels of

glutamate have been associated with both toxic and neurotrophic effect. The high levels lead to glutamate accumulation extracellularly which overstimulates the glutamatergic receptors.

This leads to production of reactive and excitotoxic nitrogen/oxygen, inducing oxidative stress that leads to neuronal death (Poletti et al., 2014), and potentially volume reduction observed in patients with CT.

5. Conclusion

Our overview of the literature on the relationship between a history of CT and structural brain volumes in BD rendered several results including a history of CT being associated with reduced GMV in hippocampus (bilateral), thalamus (bilateral), insula (bilateral), corpus callosum (bilateral), precentral gyrus (bilateral), temporal gyrus (left), fusiform gyrus (right) and frontal gyrus (bilateral). Looking at the HC subgroup with a history of CT two of the studies found an association between CT and reduced GMV in amygdala and hippocampus. A conflicting result of increased GMV was observed in BD with CT in amygdala and

hippocampus. Even though overlapping results were observed in several of the studies there were also contrasting results found. Studies were comprised of small sample sizes and a history of childhood trauma was measured using retrospective design with a inherit weakness of recall bias. Furthermore, studies applied different methodology and covariates in their analyses which may have influenced the results. Due to these limitations, it is too early to draw a conclusion on whether the reason for the reduction in GMV observed is due to a higher prevalence of CT among BT patients. It appears CT has a negative effect on the GMV in the BD group, but the results observed in this review varies between studies, and are not sufficient to draw a conclusion.

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