Changes in default mode network connectivity in the months following a motor vehicle collision The University of Toledo The University of Toledo Digital Repository Theses and Dissertations 2013 Change[.]
Aim of Study
Purpose
Despite extensive research on the default mode network (DMN) connectivity in individuals with acute and chronic traumatic stress (Bluhm, Williamson et al 2009), there is a lack of studies exploring how the DMN's functional connectivity evolves over the weeks and months after trauma in relation to reported stress symptoms.
Functional connectivity measures the synchronization of spontaneous fluctuations across different brain regions, with researchers suggesting that these fluctuations in the Default Mode Network (DMN) prepare the brain for internal thought processes Investigating how stress impacts the DMN's functional connectivity could lead to cognitive techniques that support psychological recovery from trauma Our study examined the DMN's functional connectivity at two intervals for individuals involved in motor vehicle collisions (MVCs), utilizing resting-state functional magnetic resonance imaging (fMRI) scans and Posttraumatic Stress Disorder Checklist (PCL) surveys conducted two weeks and three months post-collision.
We assessed the functional connectivity of the default mode network (DMN) by analyzing the activity in the posterior cingulate cortex (PCC), a key component of the DMN, in relation to the activity across the entire brain.
Introduction to the Default Mode Network
The Default Mode Network (DMN), as described by Van Dijk et al (2010), is an intrinsic connectivity network comprising brain regions with inherent white matter connections, shared functions, and synchronized oscillatory activity This activity can be assessed through functional imaging, which provides insights into metabolic processes Functional connectivity, defined as the temporal correlation of neurophysiological indices across different brain areas (Friston et al 1993), is investigated through correlation analyses of oscillatory activity using blood oxygen level dependent (BOLD) imaging Higher positive correlations indicate greater connectivity, suggesting parallel processing of related information, with some researchers proposing that these oscillations facilitate the temporal binding of information.
Extensive research has shown that different features of the visual field are processed in separate regions of the visual cortex (Engel, Fries et al 2001; Engel, Konig et al 1992) Current interpretations suggest that brain oscillations reflect prior usage of these regions and prepare them for future tasks (Fox and Raichle 2007) BOLD imaging studies have established that the default mode network (DMN) exhibits oscillatory activity within the frequency range of 0.1-0.01 Hz (van den Heuvel and Pol 2010) Furthermore, two sub-networks of the DMN have been identified, which operate 180° out of phase, known as the task negative (TN) network and the task positive (TP) network, based on their opposing functions (Uddin, Kelly et al 2009; Sonuga-Barke and Castellanos 2007).
The default mode network (DMN), which includes the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex (PCC), bilateral hippocampi, parahippocampi, lateral temporal cortices (LTCs), and bilateral inferior parietal cortices (IPCs)/visual cortices, shows decreased metabolic activity during goal-directed activities requiring focused attention, although characteristic oscillations persist with reduced intensity In contrast, the task-positive (TP) network demonstrates increased metabolic activity during such tasks Research on the DMN's role in psychiatric disorders has largely concentrated on the TP network, with many scholars defining the DMN exclusively in terms of the TP component This study will similarly refer to the DMN as the TP DMN.
Hypotheses
To evaluate alterations in the Default Mode Network (DMN), resting-state scans were conducted on MVC subjects two weeks and three months post-accident During these scans, participants were instructed to relax and allow their thoughts to flow freely The study analyzed correlations between functional connectivity to the posterior cingulate cortex (PCC) and scores from the Posttraumatic Stress Disorder Checklist (PCL), a self-reported tool for assessing stress symptoms, to measure changes in the DMN and emotion regulation areas in relation to stress over time.
Two weeks after experiencing trauma, the default mode network (DMN) regions are believed to be prepared for responding to future threats, indicated by heightened connectivity to the posterior cingulate cortex (PCC) The medial prefrontal cortex (mPFC) becomes active during future planning and emotional regulation (Spreng and Grady 2010) We propose that following a motor vehicle collision (MVC), the mPFC is primed to anticipate potential future threats.
4 in healthy individuals, it will aid in down-regulating negative emotions that lead to distraction The ACC also plays an important role in down-regulating emotions
Activation of the ACC down-regulates the fear-related response in the amygdalae
The anterior cingulate cortex (ACC) is expected to down-regulate negative emotions, while the hippocampi are activated during the retrieval of episodic memories, leading to intrusive recollections of trauma, particularly in the acute stress phase This phase is characterized by heightened priming of the hippocampi Additionally, following a traumatic event, the priming of the insular and visual cortices increases, which is linked to hyper-vigilance symptoms associated with stress, resulting in enhanced connectivity in the posterior cingulate cortex (PCC) However, three months post-trauma, as the initial stress subsides, both the priming of the default mode network (DMN) regions and PCC connectivity are expected to decrease.
We proposed two hypotheses to explore the aforementioned perspectives Our first hypothesis suggested a statistically significant reduction in PCC connectivity to DMN brain regions when comparing the two-week and three-month scans.
We conducted single sample T-tests on the two-week and three-month PCC connectivity maps, as well as the change in connectivity maps for subjects who recovered from MVCs Additionally, we hypothesized a positive correlation between functional connectivity to DMN brain regions and stress scores, examining correlations between the two-week PCC connectivity and initial stress scores, as well as the three-month connectivity.
5 month connectivity and final stress scores, and the change in PCC connectivity and the change in stress scores.
Overview of MRI Physics, Stress, and the Default Mode Network Literature 5
This study's results necessitate an understanding of diagnostic medical physics, psychology, and functional neuroscience Medical physics elucidates the acquisition of MRI images and the information they convey, particularly through high magnetic fields that alter subatomic properties and the manipulation of these properties via magnetic field gradients and radiofrequency pulses The introduction details echo planar imaging, the pulse sequence predominantly used in fMRI studies, and explains how the hemodynamic response reflects neural metabolism to provide insights into cognitive processes The psychology section addresses stress symptoms and their physiological implications, including diagnostic criteria for acute stress disorder and PTSD Subsequent sections explore the correlation between stress symptoms and brain activation changes, focusing on the default mode network (DMN) and limbic system regions relevant to stress literature This section summarizes findings from various studies, including animal research and fMRI investigations, while the final section traces the history of the DMN and its discovery.
6 techniques used to study it, and recent research into its role in psychiatric disorders Section 1.5 also summarizes recent studies investigating the effects of stress on the DMN.
Physics
General MRI Physics
To grasp the concept of fMRI, one must first comprehend the principles of magnetic resonance physics Charged particles have intrinsic spins represented by spin vectors, whose direction is dictated by the right-hand rule of classical physics MRI leverages the properties of spinning protons in hydrogen to create images When placed in a uniform magnetic field, hydrogen protons align both parallel and anti-parallel to the field lines, although this alignment is not absolute; the proton spin vectors precess around the magnetic field lines (Bushberg 2012).
The alignment of the particles can be explained in part by classical physics, in which spinning charged particles are approximated by tiny loops of current
Electrodynamics states that moving charges in a current experience a force in a magnetic field, leading to torque on a small current loop This torque causes the loop to rotate and align its central axis with the magnetic field The right-hand rule of electrodynamics is used to determine the direction of current flow around the loop.
The classical model fails to fully explain the behavior of spinning particles, necessitating the introduction of quantum mechanical principles Quantum exclusion rules prevent spin vectors from perfectly aligning with the magnetic field, creating an angle between the magnetic field line and the spin vector that is inversely related to the magnetic field strength In contrast, the precessional frequency of the particle is directly proportional to the magnetic field strength, with the gyromagnetic ratio γ serving as the constant that relates the two Specifically, the precessional frequency of a hydrogen proton in a magnetic field is known as hydrogen's Larmor frequency, denoted as f0.
According to quantum mechanics, a spinning charge in a magnetic field can exist in only two energy states In the lower energy state, the particle's spin vector precesses around an axis that is parallel to the magnetic field lines, while in the higher energy state, it precesses in the opposite direction The energy difference between these two states is significant for protons.
In a 1.5T magnetic field, commonly used in medical MRI scanners, the energy of an RF photon corresponds to the Larmor frequency of the proton.
Textbooks define the spin, or isochromate, as the sum of proton spin vectors within an infinitesimal volume Thermal fluctuations cause some protons to occupy higher energy states, resulting in a scenario where, in a 1.5T magnetic field, 1,000,004 protons precess parallel to the field for every 1,000,000 that precess antiparallel Consequently, the overall spin aligns with the direction of the applied magnetic field When protons are excited by radio waves matching the transition energy between their states, a greater number of protons rotate antiparallel, leading to a net rotation of the spin towards the opposite pole The angle by which the spin vector is flipped is influenced by the duration and polarization of the RF pulse, while the polarization also affects the phase of hydrogen protons in the excited volume.
The magnetic properties of a material are primarily characterized by two key quantities: the T1 and T2 relaxation time constants The T1 relaxation time constant indicates the duration needed for the longitudinal component of the spin, Mz, to reach 63% of its equilibrium value, M0 The relationship between these values can be expressed through a specific equation that defines the magnitude of the spin at any given time.
The T1 magnitude is influenced by the number of interactions between spins and the vibration states of a material Materials exhibiting a high number of vibration states with frequencies close to the Larmor frequency tend to have lower T1 values.
The T2 constant represents the time needed for spins to dephase due to spin-spin interactions, which occurs when protons in a small volume precess at varying speeds, leading to a loss of synchronization This results in a decrease in the transverse spin component, the part of the spin vector perpendicular to the longitudinal component, over time Dephasing is driven by slight variations in local magnetic field strength that affect the precessional speeds of protons, with interactions between protons causing these spin-spin interactions Direct measurement of T2 is challenging due to inhomogeneities in the main magnetic field, which also influence the precessional frequencies of protons Consequently, the combined effects of spin-spin interactions and field inhomogeneities are represented by the T2* time constant The change in the transverse component over time can be modeled by a specific equation.
Directing radio waves at a material within a uniform magnetic field transfers energy into its lattice To achieve thermodynamic equilibrium, this energy is reemitted as additional RF photons While some of these photons are absorbed by the material's lattice, others are emitted outward When the emitted photons match the energy levels of the absorbed ones, a balance is established.
In the 10 phase, hydrogen protons in the material precess in synchrony, resulting in a constructively added signal that can be detected by an antenna This unique property enables MRI scanners to gather information about the scanned object and generate an image However, it is important to note that as the spins dephase, the intensity of the signal diminishes.
An MRI scanner employs high-intensity magnetic fields and radio wave technology to create detailed images of objects, particularly for medical imaging Most hospitals use superconducting magnets with strengths ranging from 1.5 to 3T, utilizing Nb-Ti coils to generate these magnetic fields These coils are housed within the scanner's doughnut-shaped gantry, where their arrangement aligns the magnetic field with the gantry's internal axis Additionally, gradient coils are incorporated to produce linearly varying magnetic fields along three axes, facilitating image acquisition when combined with radio frequency pulses.
In general purpose MRI imaging, three magnetic gradients—slice select, phase encode, and frequency encode—are utilized to encode spin information, corresponding to the x, y, and z gradients To select an imaging slice in the human body, coils generate a linear magnetic field gradient, which increases the precession rate of spins in the same direction Consequently, when a limited bandwidth radio wave is applied, only the spins within a specific plane that match the precession frequencies of the radio waves are excited, causing the spins to flip away from equilibrium.
A π/2 pulse rotates the net magnetization vector 90° into a plane perpendicular to the equilibrium vector Following this, a brief phase encode gradient is applied, causing excited spins to precess at varying rates before returning to their original frequency, resulting in linear phase variation along the gradient axis As the spins begin to dephase, the slice select gradient is reapplied with a π RF pulse, rephasing the spins and generating a detectable RF signal Subsequently, a frequency encode gradient is introduced to enhance the precession rate of hydrogen protons along another axis, leading to radio waves that vary by position This RF signal contains crucial information about the spins' magnitudes and locations within the selected slice, which can be utilized to create an image when combined with additional data.
To reconstruct an image of the selected slice, the signal from the receive antennae must be processed by transforming it to the spin rotating frame of reference and sampling the data This process yields a single line of data in k-space, which is essential for Fourier image reconstruction Collecting a sufficient number of lines in k-space is crucial, as a Fourier transform of the acquired data matrix ultimately generates the slice image.
Echo Planar Imaging
Echo planar imaging is a rapid imaging technique commonly employed in BOLD studies, typically utilizing a repetition time (TR) of 1 to 3 seconds This method begins with a π/2 radio frequency pulse, followed by the application of a phase encode gradient at regular intervals to increment the spins' phase Multiple echoes are generated by alternating between positive and negative lobes of the readout gradient in sync with the phase encode gradient, allowing spins to rephase and restore the signal for each echo The resulting image is T2* weighted, as gradient-mediated phase reversals do not fully compensate for magnetic field inhomogeneities A single pulse sequence captures all k-space lines for one slice in about 100 milliseconds, and with multi-slice acquisition, an entire volume can be obtained every 3 seconds The effective echo time (TE) in an echo planar sequence is defined as the duration from the initial excitation pulse to the echo time when the origin of k-space is encoded for a single slice.
To maximize the number of volumes and the signal per voxel, echo planar slice dimensions are generally set at 64 by 64, with voxel sizes of 3mm by 3mm by 5mm (Poustchi-Amin, Mirowitz et al 2001; Buxton 2002).
Blood Oxygen Level Dependent Imaging
Hemoglobin is a complex protein that transports oxygen in the bloodstream, consisting of four amino acid strands each bound to an iron atom, which facilitates oxygen binding The oxygenated form of hemoglobin has four receptor sites for oxygen, and when erythrocytes encounter bicarbonate ions, oxygen is released into the blood plasma and diffuses to oxygen-requiring neurons As oxygen is released, the iron's oxygenation state changes; oxyhemoglobin has paired electrons, while deoxyhemoglobin has unpaired electrons These unpaired electrons, similar to protons in hydrogen nuclei, are spinning particles that cause small changes in the local magnetic field when hemoglobin is placed in a strong uniform magnetic field.
BOLD imaging leverages the magnetic properties of hemoglobin to examine brain region activation during various tasks When neurons fire action potentials, their metabolism rises to support Na+ and K+ protein pumps for membrane repolarization, leading to carbon dioxide release into the bloodstream This carbon dioxide is converted to bicarbonate ions for transport to the lungs Several mechanisms, such as smooth muscle relaxation in blood vessels due to reduced blood oxygen and feedback from vessel introceptors, trigger vessel dilation in response to these changes Consequently, there is an increase in oxygenated blood flow to areas with heightened neural metabolic activity This hemodynamic response overcompensates for the initial decrease in blood oxygenation caused by brain activation, resulting in an influx of oxygen that surpasses the activation's requirements, ultimately decreasing magnetic susceptibility.
The RF signal intensity in the region increases, leading to a hemodynamic response that is usually delayed by one to two seconds following metabolic activation, lasting for two to four seconds (Buxton, Uludag et al 2004).
The Stress Response and Trauma Related Stress Disorders
Stress Response
In "The Clinical Guide to the Treatment of the Human Stress Response," George Everly and Jeffrey Lating describe the neural and physiological processes that initiate the human stress response Their model identifies three key phases: cognitive appraisal, cognitive affective integration, and neurological triggering.
Sensory stimuli are initially gathered and transmitted to the limbic system, where higher-order processing centers like the mPFC and ACC evaluate the information These regions determine whether stimuli are stressors or non-stressors through a complex classification process influenced by biological factors, personality traits, and past experiences This classification affects the generation of affect, which in turn shapes cognitive processing Notably, an individual's current emotional state can impact their appraisal; for instance, someone experiencing stress is more prone to perceive ambiguous stimuli as threatening.
When cognitive appraisal and affect integration identify a stimulus as a stressor, various neurological mechanisms can initiate the stress response These mechanisms are categorized into three groups: neural mechanisms, neuroendocrine mechanisms, and endocrine mechanisms, arranged by the increasing duration of their effects.
The neural mechanisms activate the sympathetic nervous system via the hypothalamus and skeletal muscular system, leading to various physiological responses This activation increases heart rate and contractility, constricts skin and visceral blood vessels, dilates vessels in skeletal muscles, enlarges pupils, opens lung bronchi, promotes glycogenolysis, and suppresses digestion Additionally, the innervation of skeletal muscles enhances muscle tone, preparing the body for action.
The activation of the neuroendocrine system triggers the fight or flight response, primarily facilitated by the amygdalae Efferent fiber tracts connect the amygdala to the hypothalamus, ultimately reaching the adrenal gland This stimulation of the adrenal complex plays a crucial role in the body's stress response.
16 leads to the secretion of the catecholamines norepinephrine and epinephrine These produce the same physiological effects as the sympathetic nervous system, but for a longer duration
Research suggests that four primary endocrine glands are activated in response to stress: the adrenal cortices, the anterior pituitary, the posterior pituitary, and the thyroid
The adrenal cortices are crucial in understanding stress disorders, as they respond to stressors by activating the hypothalamus through the hippocampus This process triggers the release of corticotrophin-releasing factor, which prompts the pituitary gland to secrete adrenocorticotropic hormone The adrenal cortex then releases glucocorticoids, including cortisol, into the bloodstream While cortisol mimics the effects of the sympathetic nervous system, prolonged exposure can weaken the immune system and contribute to feelings of helplessness.
The stress response activates to disrupt homeostasis, preparing the body for threats Once external stressors are removed, this response typically ends, allowing for a return to balance However, chronic stress and specific risk factors can impair the body's ability to regain homeostasis, potentially resulting in stress-related illnesses and psychological disorders The hippocampus is particularly vulnerable, as it can be damaged by elevated cortisol levels.
Acute Stress Disorder
Acute stress disorder can be diagnosed shortly after a traumatic event The DSM IV TR outlines eight specific criteria that an individual must meet to receive this diagnosis Criterion A is essential for the assessment process.
Acute stress disorder (ASD) arises after individuals experience or witness a traumatic event that evokes feelings of fear or horror, with specific criteria outlined in the DSM IV Key symptoms include dissociation, re-experiencing, avoidance, and hyper-arousal, with dissociative symptoms being more prominent in ASD than in PTSD To be diagnosed with ASD, individuals must exhibit at least three of five dissociative symptoms, such as emotional numbing and dissociative amnesia Other symptoms encompass intrusive thoughts, nightmares, and avoidance of trauma reminders, alongside hyper-arousal symptoms like irritability and hyper-vigilance Importantly, these symptoms must significantly impair social and occupational functioning.
Criterion G states that symptoms must persist for at least two days and no longer than four weeks; if they exceed four weeks, a PTSD diagnosis is warranted Additionally, criterion H indicates that symptoms should not be attributed to other factors like substance abuse or medical conditions In this study, all participants displayed acute stress symptoms as assessed by the PCL.
Posttraumatic Stress Disorder
Posttraumatic stress disorder as the name implies is a chronic anxiety disorder which occurs in response to a trauma The trauma to which individuals are exposed may
Trauma can be classified into two types: type I and type II Type I trauma involves a single non-interpersonal event that endangers an individual's physical wellbeing, such as surviving a major earthquake or being involved in a motor vehicle collision (MVC) In contrast, type II trauma consists of a series of interpersonal events that threaten physical wellbeing, with repeated childhood physical abuse serving as a prime example Research indicates that individuals who experience type II trauma are at a higher risk of developing PTSD compared to those who endure type I trauma Moreover, even if they do not initially develop PTSD, they are more susceptible to it following subsequent traumatic events.
To be diagnosed with PTSD, individuals must meet seven criteria, similar to acute stress disorder Criterion A requires that they have experienced or witnessed a traumatic event involving the threat of death or bodily harm, leading to feelings of fear or horror Symptoms of PTSD are categorized into three groups: re-experiencing, avoidance, and hyper-arousal A diagnosis necessitates at least one re-experiencing symptom, which can include intrusive memories, recurring nightmares, a sense of reliving the trauma, psychological distress from reminders, or physiological reactions to those reminders Additionally, the individual must exhibit at least three avoidance symptoms, such as steering clear of trauma-related thoughts, avoiding reminders, or having difficulty recalling the event.
Post-traumatic stress disorder (PTSD) is characterized by symptoms such as trauma, diminished interest in significant activities, feelings of detachment, a restricted range of emotions, and a "sense of a foreshortened future." Some researchers debate whether memory impairment related to trauma should be classified as an avoidance symptom due to physiological changes that affect memory To be diagnosed with PTSD, an individual must exhibit at least two of five arousal symptoms, including difficulty sleeping, irritability, concentration issues, hyper-vigilance, and an exaggerated startle response Symptoms must persist for a minimum of one month after the trauma for a PTSD diagnosis; otherwise, it is classified as acute stress disorder PTSD can be categorized as simple or complex, with simple PTSD focusing more on hyper-arousal and avoidance symptoms, while complex PTSD includes more dissociative and re-experiencing symptoms, often resulting from type II trauma.
1.4 Review of the Anatomy and Functional Characteristics of Regions of Importance in the Default Mode Network and Stress
This section outlines the characteristics of the brain regions examined in this study, detailing their normal functions under various conditions and their responses to stress This information establishes a context for interpreting the study's findings.
Prefrontal Cortex
The PFC has some of the most diverse functions of all of the brain regions
Generally, the size of the PFC in species is directly related to the complexity of their
Social interactions are crucial for various social processing tasks, as evidenced by fMRI studies indicating their role in theory of mind, self-referential thought, and social planning (Spreng and Grady 2010).
Previous fMRI studies have linked the dorsolateral prefrontal cortex (dlPFC) to working memory and the learning of new tasks In their research, Mason and Norton (2007) explored the relationship between daydreaming and task performance by having subjects complete verbal reasoning tasks across multiple scanning sessions After training the subjects over four sessions, they were scanned while also taking psychometric surveys to assess daydreaming tendencies during both familiar and novel tasks The findings revealed a positive correlation between daydreaming and activation in the default mode network (DMN) regions, leading to increased connectivity with the medial prefrontal cortex (mPFC) This connectivity was further associated with self-reported daydreaming frequency during the scans.
Research has linked changes in the default mode network (DMN) to various psychiatric disorders, particularly depression Studies indicate that individuals with depression exhibit heightened activation of the medial prefrontal cortex (mPFC) when processing negative words, suggesting its significant role in social cognition and self-referential thought A hallmark of depression is uncontrolled rumination, where individuals obsessively reflect on past memories, often leading to negative emotions, a process supported by the mPFC.
Research has shown that mindfulness meditation affects the default mode network (DMN) in practitioners (Taylor, Daneault et al 2013) This meditation technique encourages individuals to concentrate on their sensory experiences and perceive their thoughts as fleeting, promoting observation without attachment Advocates argue that this practice enhances present-moment awareness and reduces future-related anxiety Studies indicate that seasoned meditators demonstrate reduced connectivity in the medial prefrontal cortex (mPFC), a brain area associated with self-awareness and future planning.
Interpreting the connectivity between the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC) presents challenges, particularly as decreased connectivity is observed in various mental disorders Additionally, heightened PCC connectivity to the mPFC correlates with depressive rumination and the acquisition of new tasks Therefore, it is crucial to consider the subject pool and the context of the measurements when analyzing connectivity results related to the prefrontal cortex.
Anterior Cingulate Cortex
The anterior cingulate cortex (ACC) is crucial for emotion regulation and is often considered part of the limbic system, with its functions divided into rostral and dorsal divisions (Etkin, Egner et al 2006) The rostral division is engaged during specific emotional processing, while the dorsal division is involved in analytical tasks Research on stress disorders has highlighted the rostral division's role in emotion dysregulation (Kim, Chey et al 2008) A common experimental method to activate the ACC is the Stroop test, where participants must focus on identifying a word or image that meets specific criteria while disregarding other information For example, the emotional counting Stroop test requires subjects to count the number of emotional words presented.
Certain words displayed on a screen can evoke different emotional responses; neutral terms like "table" or "lamp" contrast with negative ones such as "explosion" or "body bag." Research indicates that individuals with PTSD exhibit heightened activation in the anterior cingulate cortex (ACC) when exposed to trauma-related words (Shin, Whalen et al 2001) Overall, those with PTSD show increased ACC activation in response to negatively connoted words, and this activation level is positively correlated with the time taken to complete a Stroop task.
fMRI imaging studies reveal that the anterior cingulate cortex (ACC) is involved in various autonomic and somatic functions, as noted by Brodal (2004) Electrical stimulation of the ACC leads to alterations in respiration, heart rate, blood pressure, and pupil dilation Additionally, it affects muscle tone and can inhibit movement, potentially linked to the fear freezing response These findings are particularly relevant for patients suffering from dissociative PTSD, as highlighted by Lanius, Vermetten, and colleagues.
2010) For example, PTSD subjects who dissociate when hearing a narrative description of their traumas demonstrate increased activation of their ACCs and decreased activation of their amygdalae.
Posterior Cingulate Cortex
The PCC, situated posterior to the corpus callosum and anterior to the precuneus, serves as a critical seed for analysis Research indicates that this area is activated during episodic memory recall, suggesting its role in a sub-network of the default mode network (DMN) that facilitates memory retrieval Additionally, connectivity studies have recognized the PCC as a major hub within the DMN, with partial correlation analyses revealing its influence on all DMN regions, except for the right medial temporal lobe.
The posterior cingulate cortex (PCC) is a crucial component of the default mode network (DMN), uniquely influencing multiple brain regions Research indicates that the PCC plays a significant role in processing visual information, particularly responding to stimuli in the peripheral visual fields and facilitating visual reorientation to these stimuli.
Inferior Parietal Cortices/Visual Cortices
The IPC and visual cortices are key components of the default mode network (DMN), playing a crucial role in the passive monitoring of visual field features These regions show activation during resting states but become deactivated when an individual directs visual attention to a specific stimulus, as highlighted by research from Shulman, Fiez, and colleagues.
Research indicates that the left angular gyrus, situated at the junction of the parietal and temporal lobes, plays a crucial role in visual processing In a study by Hahn et al (2007), activity in this region was found to be negatively correlated with response times to uncued visual targets, suggesting that the inferior parietal cortices (IPCs) and the posterior cingulate cortex (PCC) are essential for passive environmental monitoring Notably, individuals with damage to the IPCs experience Blatant's Syndrome, which impairs their ability to perceive their visual field as a whole (Buckner et al., 2008) Supporting this, studies on monkeys revealed that neuronal activity in the IPCs decreased when they focused on a localized visual stimulus, but increased when presented with a broader visual pattern, indicating the IPCs' role in integrating information across the entire visual field (Raichle et al., 2001).
Lateral Temporal Cortices
The lateral temporal cortices of the default mode network (DMN) play a crucial role in the associative processing of visual information, as they do not receive direct sensory input nor connect to subcortical motor nuclei These regions are particularly activated during tasks that require the identification of facial expressions, indicating their involvement in feature analysis of the environment Notably, electrical stimulation of these areas during surgical procedures can induce dream-like hallucinations, allowing individuals to relive past experiences, a phenomenon potentially linked to nerve tracts connecting the DMN with structures like the hippocampi and posterior cingulate cortex (PCC).
Hippocampi
The hippocampi are crucial for encoding declarative memory, particularly episodic memory, which involves recalling personal life events Bilateral ablation of the hippocampi can lead to significant anterograde and retrograde amnesia, affecting memories from one year to several years prior to the damage Anterograde amnesia occurs because the hippocampi can no longer encode new episodic memories, while retrograde amnesia arises as some memories remain in the hippocampi and have not yet transitioned to the neocortex, a process that may take about a year The encoding of new memories is believed to be enhanced by long-term potentiation, which increases the efficacy of synaptic connections through repeated excitation.
Stress negatively impacts long-term potentiation in the hippocampus (Kim and Diamond 2002) Additionally, prolonged exposure to stress hormones indirectly harms neurons by hindering their ability to recycle glutamate (Sapolsky 2000) This excess of extracellular glutamate can activate protein channels, leading to a rapid influx of Ca2+, which often results in cell death (Choi 1994).
Fluctuations in the default mode network (DMN) may enhance memory retrieval during daydreaming, reinforcing memory traces (Vincent, Snyder et al 2006) Notably, the left and right hippocampi exhibit distinct activation patterns; the left hippocampus is more active during the encoding of verbal and semantic memories, which involve knowledge of words and facts, respectively In contrast, episodic memory, related to past events and visual memories, is supported by both hippocampi, with the right hippocampus being preferentially activated for emotionally charged episodic memories (Gerdes, Wieser et al 2010) Contextual memory, which pertains to the features and arrangement of specific locations, is also supported by both hippocampi, though the right shows greater BOLD activation Autobiographical memory, encompassing episodic, semantic, and contextual information about oneself, primarily relies on the left hippocampus for encoding and retrieval due to its semantic nature (Cabeza and St Jacques 2007).
Amygdalae
The amygdalae, key components of the limbic system, play a crucial role in linking emotions to stimuli and consist of two primary nuclei: the corticomedial and basolateral nuclei The corticomedial nuclei are involved in processing taste and pain, while the basolateral nuclei focus on emotional and sensory processing Stimulation or damage to the amygdalae can lead to various physiological and emotional effects, such as a reduction in aggressive behavior observed in monkeys with amygdala damage.
Damage to the amygdalae in humans disrupts the fear response, inhibiting the activation of fight or flight mechanisms, which results in cognitive anxiety without physiological signs This impairment also affects the ability to recognize facial expressions, particularly fear In animal studies, electrical stimulation of the basolateral nuclei prompts a search for external threats, with strong stimulation eliciting fear or rage In humans, amygdala stimulation during surgery can lead to anxiety and hallucinations Additionally, amygdala damage negatively impacts emotional learning, especially in reward and punishment conditioning.
Viewing emotional faces, particularly those expressing anger or fear, triggers activation in the amygdalae (Liberzon and Martis 2006) Notably, the right amygdala shows heightened activation during the recall of emotional images (Dolcos, LaBar et al 2005) Additionally, research suggests that the amygdalae are involved in the process of fear extinction (Rauch, Shin et al 2006).
History of the Default Mode Network
Raichle introduced the concept of the default mode of brain function in his 2001 paper, proposing that a consistent pattern of brain activation occurs when an individual is at rest He noted that, despite variations in cerebral blood flow and oxygen metabolism, the brain maintains a uniform oxygen extraction factor (OEF) during this default mode Through imaging studies involving three subject groups, Raichle demonstrated that the OEF remained consistent across the brain in a resting state with eyes open He reviewed research identifying brain regions that deactivate during task performance, suggesting these areas are integral to the default mode Notably, he highlighted Shulman's meta-analysis of PET studies that pinpointed regions within the default mode network (DMN), particularly the precuneus and posterior cingulate cortex (PCC), which he argued facilitate passive environmental monitoring Supporting this, he referenced earlier studies that monitored precuneus activity in monkeys Additionally, Raichle proposed that the medial prefrontal cortex (mPFC) plays a crucial role in integrating emotional information into higher cognitive processes, asserting that the mPFC, PCC, and precuneus work together to support environmental and self-monitoring.
The initial exploration of brain region functional connectivity using BOLD imaging was conducted by Biswal in 1995, focusing on resting-state oscillations in the motor cortices Subsequently, Greicius in 2003 examined the BOLD functional connectivity of the default mode network (DMN) regions, aiming to bolster the default mode hypothesis proposed by Raichle.
28 particular, he sought to find indications of interactivity between the brain regions which were identified as being deactivated when subjects engaged in attention demanding tasks
Research shows that the default mode network (DMN) exhibits oscillations during certain unconscious states, such as the early stages of sleep and light sedation (Larson-Prior, Zempel et al 2009) However, these oscillations diminish during deep sleep (Horovitz, Braun et al 2009) Additionally, oscillations are present in patients in vegetative states but absent in those who are brain dead (Boly, Tshibanda et al 2009) These findings suggest that the DMN functions as a priming system, enabling individuals to quickly process information upon waking.
The Default Mode Network (DMN) evolves with age, showing asynchronous activity in infancy, particularly between the anterior and posterior regions Children engage less of their brain in DMN activities compared to adults, especially in the prefrontal cortex, where activation in the dorsolateral prefrontal cortex (dlPFC) is notably lower This reduced activation may indicate children's limited capacity for future planning in response to current stimuli The synchronization between the medial prefrontal cortex (mPFC) and posterior components is believed to contribute to the development of self-identity, integrating episodic memory recall with social cognition However, early life abuse may disrupt the normal development of the DMN.
In older individuals, the extent of DMN activation decreases, especially in the PCC Furthermore, there is also a gradual decrease in connectivity that occurs between
Research suggests that the degradation of white matter tracks with aging may lead to changes in the posterior and anterior portions of the default mode network (DMN), potentially contributing to natural cognitive decline (Andrews-Hanna, Snyder et al 2007).
In his paper, Sonuga-Barke proposed a neurobiological hypothesis suggesting that the Default Mode Network (DMN) may be disrupted in various pathologies, including attention deficit disorder.
Sonuga-Barke and Castellanos (2007) suggest that the Default Mode Network (DMN) can be activated at unsuitable times, leading to disruptions in attention and shifts in focus They provide evidence that task performance suffers when regions of the DMN are engaged.
Research indicates that reduced connectivity to the medial prefrontal cortex (mPFC) may signify underlying pathology, particularly in PTSD, where emotional regulation is compromised Ochsner proposed that the mPFC should be segregated from the default mode network (DMN) in individuals with PTSD, as it plays a crucial role in top-down emotional regulation This hypothesis is further supported by findings in survivors of childhood abuse, who exhibit diminished connectivity between anterior and posterior DMN regions, potentially contributing to the difficulties PTSD patients face in managing episodic memory retrieval and stress responses.
Investigators have argued that repeated abuse interrupts the development of the DMN As a result, individuals with PTSD have DMNs that more closely resemble the DMNs in children
One feature of PTSD is the disruption of memory retrieval While most PTSD patients readily recall details relating to their traumas, they have impaired memories for
Research indicates that individuals with PTSD struggle to clearly recall their traumatic experiences, leading to disrupted autobiographical memory retrieval This impairment often extends beyond the trauma itself, resulting in overgeneralized autobiographical memories The memory retrieval process is thought to occur in phases, where general memories are accessed before specific details; however, those with PTSD often have their recall interrupted before reaching the latter phase Additionally, pronounced deficits in verbal memory are common among PTSD sufferers, which may be linked to childhood trauma Studies show a negative correlation between the extent of childhood trauma and the size of the left hippocampus, suggesting that excessive stress exposure can lead to hippocampal damage.
Research indicates that abnormal connectivity within the default mode network (DMN) significantly impacts brain function For instance, individuals with autism exhibit minimal connectivity between the posterior cingulate cortex (PCC) and the medial prefrontal cortex (mPFC), which may contribute to their social impairments and disrupted self-perception The mPFC is crucial for self-referential thought and social cognition, highlighting its importance in these functions Similarly, Alzheimer's patients also demonstrate reduced connectivity to the mPFC, potentially explaining their comparable symptoms (Wermke, Sorg et al 2008).
Recently, Lanius at the University of Western Ontario carried out a MVC study similar to the present study She recruited 15 subjects who had been involved in major
A study involving 31 motor vehicle collision (MVC) subjects assessed PTSD symptoms using CAPs six and twelve weeks post-scan Nine subjects were scanned six weeks after their MVCs, while six were scanned twelve weeks later Correlation analysis indicated positive relationships between CAPs scores and PCC connectivity, particularly with the anterior cingulate cortex (ACC) during concurrent scans Additionally, PCC connectivity to the right amygdala showed a positive correlation with CAPs scores at the twelve-week mark The findings suggest that increased ACC connectivity may reflect heightened awareness of symptoms, although the reasons behind the correlation with the right amygdala remain unexplored.
A study on PTSD functional connectivity was conducted in China after an 8.0 magnitude earthquake, involving scans of subjects within 25 days post-disaster (Lui, Huang et al 2009) The research compared resting-state scans of 44 earthquake survivors with 32 control participants, revealing decreased connectivity in limbic regions, including the amygdalae and anterior cingulate cortex (ACC), as well as diminished connectivity in default mode network (DMN) regions like the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) The authors concluded that these findings align with existing PTSD literature, suggesting that reduced connectivity in limbic regions may indicate impaired emotional regulation in response to stress.
Ultimately, the last two articles present findings which are important for predicting the possible patterns of connectivity during the acute and chronic stress
Lanius's MVC paper indicates that increased PCC connectivity to the ACC is associated with stress symptoms, suggesting that awareness of these symptoms may enhance ACC priming to help regulate emotions We anticipate observing similar effects during acute stress Conversely, Lui's research points to a potential decrease in PCC connectivity to the mPFC during acute stress, although it did not explore the link between stress symptoms and PCC connectivity It is plausible that the trauma severity in the earthquake study was greater than in the MVC study, resulting in brain activation patterns linked to hyper-arousal symptoms and diminished emotion regulation.
2010) This differs from the expected PCC connectivity for individuals who eventually recover from stress and is more consistent with Ochsner's findings in the victims of childhood abuse
To conduct functional connectivity analyses, we collected resting-state MRI scans along with respiratory and heart rate data The materials section details the hardware and software used for data acquisition and processing, which included an MRI scanner, physiological acquisition devices, a paradigm computer, a goggle system, and interface devices such as cables and an optical isolator For data analysis, we utilized SPM, SPM add-ons, and SPSS The methods section provides a comprehensive overview of the data processing pipeline.
Equipment
Scanner
Subjects underwent imaging using a three-tesla GE Signa MRI scanner, while physiological data, including breathing and heart rate measurements, was collected through a pulsox and respiratory strap that interfaced directly with the MRI scanner.
Physiological data was shown on the MRI control console and transmitted via a serial cable to the paradigm computer for data collection and processing Additionally, a +5V pulse was generated through a BNC cable each time a slice was acquired by the scanner, which was utilized to synchronize data acquisition with the beginning of each resting-state scan.
Paradigm Computer
A Dell desktop PC featuring a 3 GHz Intel(R) Core(TM) Quad CPU was utilized to run Matlab and PowerPoint, manage data from the MRI scanner, and interface with the goggle system The setup included two monitors: one for the experimenter's workspace and the other for displaying images to the subject through the goggles The physiological data packets were transmitted via a serial cord connected to a serial port, while the BNC cable was linked to an optical isolator to prevent electronic feedback into the scanner This optical isolator employed a light-emitting diode and sensor to transmit signals between isolated circuits, with the diode illuminating in response to voltage input, generating a corresponding voltage pulse detected by the sensor The output from the optical isolator was then connected to the paradigm computer through a serial cable.
Goggle System
During the resting-state scan, subjects observed a white fixation cross-hair on a black background through NordicNeuroLab goggles The goggle system comprised three key components: the computer interface module, the goggle interface module, and the goggles The computer interface module, powered by an external source, connected directly to the computer via a serial port.
The goggle interface module was connected to the computer via a fiber optic cable, with the module located on the cart during subject scanning and the goggles mounted on the MRI head coil To avoid interference with the MRI receiver coils, the fiber optic cable passed through a hole in the MRI room's copper RF shield, while the module itself was positioned away from the scanner due to its ferromagnetic material.
Software
SPM
Image analyses were conducted using SPM, a Matlab software package from The Wellcome Trust Centre for Neuroimaging at University College London This software offers various tools for brain imaging analysis, including fMRI functions for preprocessing, first-level analysis, and second-level analysis Key preprocessing steps involve realignment, slice-timing correction, coregistration, normalization, and smoothing, which are elaborated on in sections 3.8-3.10.
SPM Add-Ons: xjView, Marsbar2.0, and VBM
The SPM add-ons xjView and Marsbar 2.0 were utilized for enhanced visualization of results and sophisticated region of interest analysis XjView features multiple brain atlases that facilitate the analysis of significant clusters, providing detailed insights into brain activity.
Marsbar is a powerful tool for constructing regions of interest (ROIs) and extracting data from SPM results, allowing users to create spherical ROIs, define them based on anatomical templates or imaging results, and perform set operations It also enables the extraction of mean image intensity values for these ROIs Additionally, VBM (voxel-based morphology), an SPM add-on, enhances segmentation capabilities by utilizing probability maps from previous studies to classify voxels as gray matter, white matter, or cerebral spinal fluid, facilitating the extraction of relevant masks (Ashburner and Friston 2000).
SPSS
SPSS 19 was used to analyze survey data Maintained and licensed by IBM, it provided the tools used to perform our study's statistical tests, including Pearson correlations and paired and unpaired T-tests
Recruitment
Adult patients aged 18 and older who were involved in motor vehicle collisions (MVCs) were recruited from the University of Toledo Medical Center Emergency Department Eligible participants included those with mild concussions and/or memory loss, provided they had no injuries preventing them from undergoing an MRI scan The study's nature was explained to the patients, and all participants signed a consent form that had been approved.
The University of Toledo Institutional Review Board (IRB) conducted an initial survey packet that included various psychometric instruments, such as the PCL, to assess the initial stress symptoms of the subjects.
Timeline of Subject Activities
Participants in the study underwent two MRI scans, with the first occurring within three weeks post-motor vehicle collision (MVC) and the second three to four months later Monthly survey packets, including the PCL survey, were distributed to subjects after the MVC, but only the initial and final surveys were analyzed for this study Additionally, a CAPS interview was conducted by one of two psychology students three months after the MVCs, typically on the same day as the second fMRI scan for most participants.
Positioning Subjects in Scanner
After a brief training session, subjects were prepared for the MRI scan by receiving earplugs and lying on the scanner table, where a respiratory strap was fastened around their waist An 8-channel head coil was positioned over their heads, and goggles were adjusted to ensure clear visibility of displayed text A pulsox was placed on their finger to monitor cardiac activity, and an emergency squeeze ball was provided for safety During the resting-state scan, subjects focused on a white crosshair against a black background, aligning with Raichle's conditions for optimal DMN activation.
Stress Related Surveys
Posttraumatic Stress Disorder Checklist
The Posttraumatic Stress Disorder Checklist (PCL) is a psychometric tool designed to evaluate the symptoms of PTSD as outlined in the DSM IV It includes three distinct versions: military, civilian, and specific adaptations.
The analysis focuses on symptoms stemming from a specific traumatic event, specifically a motor vehicle collision (MVC) Questions 1-5 assess diagnostic criteria B, which pertains to intrusive recollections associated with PTSD, such as whether the individual has "repeated, disturbing memories, thoughts, or images of the stressful experience." The subsequent set of questions, numbered 6-12, evaluates criteria C.
39 avoidance behavior and numbing sensations Question 7 asks whether the subject is
Avoiding activities or situations that trigger memories of stressful experiences is a common response Questions 13 to 17 assess hyper-arousal, with question 16 specifically inquiring if the individual feels "super alert or watchful or on guard." Participants answer all 17 questions using a Likert scale ranging from 1 (Not at all) to 5 (Extremely).
Clinician Administered Posttraumatic Stress Disorder Scale
The Clinician Administered Posttraumatic Stress Disorder Scale (CAPS) was conducted about three months post-collision to evaluate PTSD symptoms Developed by the National Center for PTSD, the scale includes questions that measure the severity and frequency of symptoms, their impact on social and occupational functioning, and any improvements since the last evaluation (Weathers, Ruscio et al 1999) A PTSD diagnosis requires one symptom from criteria B (re-experiencing), three from criteria C (avoidance/numbing), and two from criteria D (hyper-arousal), with total scores indicating the intensity and frequency of these symptoms.
MRI Scans
Localizer
A three-plane localizer scan was performed after positioning the subject in the scanner, allowing for the alignment of future scan slices The technologist ensured complete coverage of the cerebral cortex by aligning the slices, with sagittal planes set parallel to the hemispheric midline whenever feasible.
40 technologist also attempted to align the axial planes parallel to the top of the corpus collosum.
Resting-State fMRI
The initial resting-state scan utilized an eight minute EPI/GR protocol A total of
34 slices for 240 phases were obtained (TR 00ms, TE0ms, matrixd 64, voxel dimensions=3.75 3.75 3.5 mm).
Spoiled Gradient Echo
A high-resolution anatomical image was captured using a 3D spoiled gradient (SPGR) scan, which took 11 minutes and 15 seconds to complete The scan produced 164 axial slices with a repetition time (TR) of 7.9 ms, an echo time (TE) of 3 ms, and an inversion time (TI) of 0 ms, utilizing a matrix size of 248 and voxel dimensions of 1 x 1 x 1 mm.
Overlay
An additional T1 weighted scan was obtained to overlay the fMRI scan to the SPGR The scan lasted two minutes, recording 34 slices (TR%0, TE=3.6, flip angle°, matrix%6 256, voxel dimensions= 1 1 3.5 mm).
System Check
After positioning the subject in the scanner, we verified that the paradigm computer was successfully receiving physiological data transmitted through a standard serial cable The data packets, composed of six 16-bit integers, included an unsigned counter variable that incremented with each packet and reset upon reaching its maximum value Although the second and third integers contained data from additional cardiac leads not utilized in our setup, the fourth and fifth integers provided pulsox and respiratory data, respectively We employed Matlab to capture and record this data, ensuring the computer accurately received the incoming packets from the communication port.
Data was recorded for 10 seconds, and the integers from individual packets were rebinned and plotted in six independent graphs Graphs 3 and 4, representing the third and fourth unsigned integers in the packet, indicated cardiac and respiratory activity, confirming that the computer was successfully receiving data.