Functional Magnetic Resonance Imaging Signal Variability Is Associated With Neuromodulation in Fibromyalgia.

OBJECTIVES: Although primary motor cortex (M1) transcranial direct current stimulation (tDCS) has an analgesic effect in fibromyalgia (FM), its neural mechanism remains elusive. We investigated whether M1-tDCS modulates a regional temporal variability of blood-oxygenation-level-dependent (BOLD) signals, an indicator of the brain's flexibility and efficiency and if this change is associated with pain improvement. MATERIALS AND METHODS: In a within-subjects cross-over design, 12 female FM patients underwent sham and active tDCS on five consecutive days, respectively. Each session was performed with an anode placed on the left M1 and a cathode on the contralateral supraorbital region. The subjects also participated in resting-state functional magnetic resonance imaging (fMRI) at baseline and after sham and active tDCS. We compared the BOLD signal variability (SDBOLD), defined as the standard deviation of the BOLD time-series, between the tDCS conditions. Baseline SDBOLD was compared to 15 healthy female controls. RESULTS: At baseline, FM patients showed reduced SDBOLD in the ventromedial prefrontal cortex (vmPFC), lateral PFC, and anterior insula and increased SDBOLD in the posterior insula compared to healthy controls. After active tDCS, compared to sham, we found an increased SDBOLD in the left rostral anterior cingulate cortex (rACC), lateral PFC, and thalamus. After sham tDCS, compared to baseline, we found a decreased SDBOLD in the dorsomedial PFC and posterior cingulate cortex/precuneus. Interestingly, after active tDCS compared to sham, pain reduction was correlated with an increased SDBOLD in the rACC/vmPFC but with a decreased SDBOLD in the posterior insula. CONCLUSION: Our findings suggest that M1-tDCS might revert temporal variability of fMRI signals in the rACC/vmPFC and posterior insula linked to FM pain. Changes in neural variability would be part of the mechanisms underlying repetitive M1-tDCS analgesia in FM.

Differential alteration of fMRI signal variability in the ascending trigeminal somatosensory and pain modulatory pathways in migraine.

BACKGROUND: The moment-to-moment variability of resting-state brain activity has been suggested to play an active role in chronic pain. Here, we investigated the regional blood-oxygen-level-dependent signal variability (BOLDSV) and inter-regional dynamic functional connectivity (dFC) in the interictal phase of migraine and its relationship with the attack severity. METHODS: We acquired resting-state functional magnetic resonance imaging from 20 migraine patients and 26 healthy controls (HC). We calculated the standard deviation (SD) of the BOLD time-series at each voxel as a measure of the BOLD signal variability (BOLDSV) and performed a whole-brain voxel-wise group comparison. The brain regions showing significant group differences in BOLDSV were used to define the regions of interest (ROIs). The SD and mean of the dynamic conditional correlation between those ROIs were calculated to measure the variability and strength of the dFC. Furthermore, patients' experimental pain thresholds and headache pain area/intensity levels during the migraine ictal-phase were assessed for clinical correlations. RESULTS: We found that migraineurs, compared to HCs, displayed greater BOLDSV in the ascending trigeminal spinal-thalamo-cortical pathways, including the spinal trigeminal nucleus, pulvinar/ventral posteromedial (VPM) nuclei of the thalamus, primary somatosensory cortex (S1), and posterior insula. Conversely, migraine patients exhibited lower BOLDSV in the top-down modulatory pathways, including the dorsolateral prefrontal (dlPFC) and inferior parietal (IPC) cortices compared to HCs. Importantly, abnormal interictal BOLDSV in the ascending trigeminal spinal-thalamo-cortical and frontoparietal pathways were associated with the patient's headache severity and thermal pain sensitivity during the migraine attack. Migraineurs also had significantly lower variability and greater strength of dFC within the thalamo-cortical pathway (VPM-S1) than HCs. In contrast, migraine patients showed greater variability and lower strength of dFC within the frontoparietal pathway (dlPFC-IPC). CONCLUSIONS: Migraine is associated with alterations in temporal signal variability in the ascending trigeminal somatosensory and top-down modulatory pathways, which may explain migraine-related pain and allodynia. Contrasting patterns of time-varying connectivity within the thalamo-cortical and frontoparietal pathways could be linked to abnormal network integrity and instability for pain transmission and modulation.

High-definition tDCS over primary motor cortex modulates brain signal variability and functional connectivity in episodic migraine.

OBJECTIVE: This study investigated how high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) affects brain signal variability and functional connectivity in the trigeminal pain pathway, and their association with changes in migraine attacks. METHODS: Twenty-five episodic migraine patients were randomized for ten daily sessions of active or sham M1 HD-tDCS. Resting-state blood-oxygenation-level-dependent (BOLD) signal variability and seed-based functional connectivity were assessed pre- and post-treatment. A mediation analysis was performed to test whether BOLD signal variability mediates the relationship between treatment group and moderate-to-severe headache days. RESULTS: The active M1 HD-tDCS group showed reduced BOLD variability in the spinal trigeminal nucleus (SpV) and thalamus, but increased variability in the rostral anterior cingulate cortex (rACC) compared to the sham group. Connectivity decreased between medial pulvinar-temporal pole, medial dorsal-precuneus, and the ventral posterior medial nucleus-SpV, but increased between the rACC-amygdala, and the periaqueductal gray-parahippocampal gyrus. Changes in medial pulvinar variability mediated the reduction in moderate-to-severe headache days at one-month post-treatment. CONCLUSIONS: M1 HD-tDCS alters BOLD signal variability and connectivity in the trigeminal somatosensory and modulatory pain system, potentially alleviating migraine headache attacks. SIGNIFICANCE: M1 HD-tDCS realigns brain signal variability and connectivity in migraineurs closer to healthy control levels.

Exploring HD-tDCS Effect on µ-opioid Receptor and Pain Sensitivity in Temporomandibular Disorder: A Pilot Randomized Clinical Trial Study.

This study explored the association between experimentally-induced pain sensitivity and µ-opioid receptor (µOR) availability in patients with temporomandibular disorder (TMD) and further investigated any changes in the pain and µOR availability following high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) with pilot randomized clinical trials. Seven patients with TMD completed either active (n = 3) or sham treatment (n = 4) for 10 daily sessions and underwent positron emission tomography (PET) scans with [11C]carfentanil, a selective µOR agonist, a week before and after treatment. PET imaging consisted of an early resting and late phase with the sustained masseteric pain challenge by computer-controlled injection of 5% hypertonic saline. We also included 12 patients with TMD, obtained from our previous study, for baseline PET analysis. We observed that patients with more sensitivity to pain, indicated by lower infusion rate, had less µOR availability in the right amygdala during the late phase. Moreover, active M1 HD-tDCS, compared to sham, increased µOR availability post-treatment in the thalamus during the early resting phase and the amygdala, hippocampus, and parahippocampal gyrus during the late pain challenge phase. Importantly, increased µOR availability post-treatment in limbic structures including the amygdala and hippocampus was associated with decreased pain sensitivity. The findings underscore the role of the µOR system in pain regulation and the therapeutic potential of HD-tDCS for TMD. Nonetheless, large-scale studies are necessary to establish the clinical significance of these results. TRIAL REGISTRATION: ClinicalTrial.gov (NCT03724032) PERSPECTIVE: This study links pain sensitivity and µ-opioid receptors in patients with TMD. HD-tDCS over M1 improved µOR availability, which was associated with reduced pain sensitivity. Implications for TMD pain management are promising, but larger clinical trials are essential for validation.

Management of Episodic Migraine with Neuromodulation: A Case Report.

Migraine is a highly prevalent neurovascular disorder that affects approximately 15% of the global population. Migraine attacks are a complex cascade of neurologic events that lead to debilitating symptoms and are often associated with inhibitory behavior. The constellation of severe signs and symptoms during the ictal phase (headache attack) makes migraine the third most common cause of disability globally in both sexes under the age of 50. Misuse of pharmaceuticals, such as opiates, can lead to devastating outcomes and exacerbation of pain and headache attacks. A safe and well-tolerated non-pharmacological research approach is high-definition transcranial direct current stimulation over the M1.

Classifying migraine using PET compressive big data analytics of brain's µ-opioid and D2/D3 dopamine neurotransmission.

Introduction: Migraine is a common and debilitating pain disorder associated with dysfunction of the central nervous system. Advanced magnetic resonance imaging (MRI) studies have reported relevant pathophysiologic states in migraine. However, its molecular mechanistic processes are still poorly understood in vivo. This study examined migraine patients with a novel machine learning (ML) method based on their central µ-opioid and dopamine D2/D3 profiles, the most critical neurotransmitters in the brain for pain perception and its cognitive-motivational interface. Methods: We employed compressive Big Data Analytics (CBDA) to identify migraineurs and healthy controls (HC) in a large positron emission tomography (PET) dataset. 198 PET volumes were obtained from 38 migraineurs and 23 HC during rest and thermal pain challenge. 61 subjects were scanned with the selective µ-opioid receptor (µOR) radiotracer [11C]Carfentanil, and 22 with the selective dopamine D2/D3 receptor (DOR) radiotracer [11C]Raclopride. PET scans were recast into a 1D array of 510,340 voxels with spatial and intensity filtering of non-displaceable binding potential (BPND), representing the receptor availability level. We then performed data reduction and CBDA to power rank the predictive brain voxels. Results: CBDA classified migraineurs from HC with accuracy, sensitivity, and specificity above 90% for whole-brain and region-of-interest (ROI) analyses. The most predictive ROIs for µOR were the insula (anterior), thalamus (pulvinar, medial-dorsal, and ventral lateral/posterior nuclei), and the putamen. The latter, putamen (anterior), was also the most predictive for migraine regarding DOR D2/D3 BPND levels. Discussion: CBDA of endogenous µ-opioid and D2/D3 dopamine dysfunctions in the brain can accurately identify a migraine patient based on their receptor availability across key sensory, motor, and motivational processing regions. Our ML-based findings in the migraineur's brain neurotransmission partly explain the severe impact of migraine suffering and associated neuropsychiatric comorbidities.

Effect of High-Definition Transcranial Direct Current Stimulation on Headache Severity and Central µ-Opioid Receptor Availability in Episodic Migraine.

Objective: The current understanding of utilizing HD-tDCS as a targeted approach to improve headache attacks and modulate endogenous opioid systems in episodic migraine is relatively limited. This study aimed to determine whether high-definition transcranial direct current stimulation (HD-tDCS) over the primary motor cortex (M1) can improve clinical outcomes and endogenous µ-opioid receptor (µOR) availability for episodic migraineurs. Methods: In a randomized, double-blind, and sham-controlled trial, 25 patients completed 10-daily 20-min M1 HD-tDCS, repeated Positron Emission Tomography (PET) scans with a selective agonist for µOR. Twelve age- and sex-matched healthy controls participated in the baseline PET/MRI scan without neuromodulation. The primary endpoints were moderate-to-severe (M/S) headache days and responder rate (≥50% reduction on M/S headache days from baseline), and secondary endpoints included the presence of M/S headache intensity and the use of rescue medication over 1-month after treatment. Results: In a one-month follow-up, at initial analysis, both the active and sham groups exhibited no significant differences in their primary outcomes (M/S headache days and responder rates). Similarly, secondary outcomes (M/S headache intensity and the usage of rescue medication) also revealed no significant differences between the two groups. However, subsequent analyses showed that active M1 HD-tDCS, compared to sham, resulted in a more beneficial response predominantly in higher-frequency individuals (>3 attacks/month), as demonstrated by the interaction between treatment indicator and baseline frequency of migraine attacks on the primary outcomes. These favorable outcomes were also confirmed for the secondary endpoints in higher-frequency patients. Active treatment also resulted in increased µOR concentration compared to sham in the limbic and descending pain modulatory pathway. Our exploratory mediation analysis suggests that the observed clinical efficacy of HD-tDCS in patients with higher-frequency conditions might be potentially mediated through an increase in µOR availability. Conclusion: The 10-daily M1 HD-tDCS can improve clinical outcomes in episodic migraineurs with a higher baseline frequency of migraine attacks (>3 attacks/month). This improvement may be, in part, facilitated by the increase in the endogenous µOR availability. Clinical Trial Registration: www.ClinicalTrials.gov, identifier - NCT02964741.

The Concept, Development, and Application of a Home-Based High-Definition tDCS for Bilateral Motor Cortex Modulation in Migraine and Pain.

Whereas, many debilitating chronic pain disorders are dominantly bilateral (e.g., fibromyalgia, chronic migraine), non-invasive and invasive cortical neuromodulation therapies predominantly apply unilateral stimulation. The development of excitatory stimulation targeting bilateral primary motor (M1) cortices could potentially expand its therapeutic effect to more global pain relief. However, this is hampered by increased procedural and technical complexity. For example, repetitive transcranial magnetic stimulation (rTMS) and 4 × 1/2 × 2 high-definition transcranial direct current stimulation (4 × 1/2 × 2 HD-tDCS) are largely center-based, with unilateral-target focus-bilateral excitation would require two rTMS/4 × 1 HD-tDCS systems. We developed a system that allows for focal, non-invasive, self-applied, and simultaneous bilateral excitatory M1 stimulation, supporting long-term home-based treatment with a well-tolerated wearable battery-powered device. Here, we overviewed the most employed M1 neuromodulation methods, from invasive techniques to non-invasive TMS and tDCS. The evaluation extended from non-invasive diffuse asymmetric bilateral (M1-supraorbital [SO] tDCS), non-invasive and invasive unilateral focal (4 × 1/2 × 2 HD-tDCS, rTMS, MCS), to non-invasive and invasive bilateral bipolar (M1-M1 tDCS, MCS), before outlining our proposal for a neuromodulatory system with unique features. Computational models were applied to compare brain current flow for current laboratory-based unilateral M11 and bilateral M12 HD-tDCS models with a functional home-based M11-2 HD-tDCS prototype. We concluded the study by discussing the promising concept of bilateral excitatory M1 stimulation for more global pain relief, which is also non-invasive, focal, and home-based.

Structural and functional thalamocortical connectivity study in female fibromyalgia.

Dysfunctional thalamocortical interactions have been suggested as putative mechanisms of ineffective pain modulation and also suggested as possible pathophysiology of fibromyalgia (FM). However, it remains unclear which specific thalamocortical networks are altered and whether it is related to abnormal pain perception in people with FM. Here, we conducted combined vertex-wise subcortical shape, cortical thickness, structural covariance, and resting-state functional connectivity analyses to address these questions. FM group exhibited a regional shape deflation of the left posterior thalamus encompassing the ventral posterior lateral and pulvinar nuclei. The structural covariance analysis showed that the extent of regional deflation of the left posterior thalamus was negatively covaried with the left inferior parietal cortical thickness in the FM group, whereas those two regions were positively covaried in the healthy controls. In functional connectivity analysis with the left posterior thalamus as a seed, FM group had less connectivity with the periaqueductal gray compared with healthy controls, but enhanced connectivity between the posterior thalamus and bilateral inferior parietal regions, associated with a lower electrical pain threshold at the hand dorsum (pain-free point). Overall, our findings showed the structural thalamic alteration interacts with the cortical regions in a functionally maladaptive direction, leading the FM brain more responsive to external stimuli and potentially contributing to pain amplification.

Dopaminergic Regulation of Reward System Connectivity Underpins Pain and Emotional Suffering in Migraine.

PURPOSE: It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered reward system connectivity is directly associated with clinical manifestations, including negative affect and ictal pain severity and, at the molecular level, the dopamine (DA) D2/D3 receptors (D2/3Rs) signaling implicated in encoding motivational and emotional cues. PATIENTS AND METHODS: We acquired resting-state functional MRI from interictal episodic migraine (EM) patients and age-matched healthy controls, as well as positron emission tomography (PET) with [11C]raclopride, a selective radiotracer for DA D2/3Rs, from a subset of these participants. The nucleus accumbens (NAc) was seeded to measure functional connectivity (FC) and DA D2/3Rs availability based on its essential involvement in pain-related aversive/reward functions. Associations of the brain measures with positive/negative affect and ictal pain severity were also assessed. RESULTS: Compared with controls, the EM group showed weaker right NAc connectivity with areas implicated in pain and emotional regulation, such as the amygdala, rostral anterior cingulate cortex, hippocampus, and thalamus; but showed stronger left NAc connectivity with the dorsolateral prefrontal cortex and lingual gyrus. Moreover, among the altered NAc connectivities, only right NAc-amygdala connectivity was inversely correlated with DA D2/3Rs availability in migraine patients (diagnostic group-by-D2/3Rs interaction p < 0.007). At a clinical level, such weaker NAc-amygdala connectivity was associated with lower interictal positive affect and greater ictal pain severity over the head and facial extension area (pain area and intensity number summation, PAINS). CONCLUSION: Together, our findings suggest that altered reward system connectivity, specifically between the NAc and amygdala, might be affected by endogenous DA D2/3Rs signaling, and such process might be a neural mechanism that underlies emotional and pain suffering in episodic migraineurs.

Decreased GABA levels in anterior cingulate and basal ganglia in medicated subjects with panic disorder: a proton magnetic resonance spectroscopy (1H-MRS) study.

The purpose of this study was to investigate the brain gamma-aminobutyric acid (GABA) concentration and its relationship with clinical variables in patients with panic disorder (PD). Single voxel proton magnetic resonance spectroscopy ((1)H-MRS) scan was performed on 22 medicated subjects with PD and 25 age and sex-matched healthy comparison subjects. GABA and other metabolite levels were measured in the anterior cingulate cortex (ACC) and basal ganglia. GABA levels were significantly lower in the ACC and basal ganglia of PD patients relative to comparison subjects. Lactate and choline concentrations in the ACC in PD patients were also higher than in the comparison subjects. Our data suggested in part that alterations of the GABA function and the energy metabolism in ACC and basal ganglia may play an important role in the pathophysiology of panic disorder.

Clinical response of quetiapine in rapid cycling manic bipolar patients and lactate level changes in proton magnetic resonance spectroscopy.

The aim of the current study was to evaluate the relationship between quetiapine's effect on the improvement of mood symptoms in bipolar patients and brain metabolite level changes as measured by proton magnetic resonance spectroscopy ((1)H-MRS). Rapid cycling bipolar patients in the manic state were recruited and treated with quetiapine for 12 weeks. Clinical assessment was performed using the Young Mania Rating Scale (YMRS), the 17-item Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression-Severity scale (CGI-S) at baseline and weekly intervals during the 12-week period. In order to evaluate metabolite level changes over time, (1)H-MRS scans were acquired at baseline and week 12. There were significant reductions in YMRS scores (by 43.0%), HDRS scores (by 27.5%) and CGI-S score (by 44.6%) over the 12 week-period. Lactate levels significantly decreased over the 12-week study period (22.4%). This change in lactate levels was more prominent in quetiapine responders than in non-responders. Additionally, there was a positive correlation between changes in lactate levels and those in YMRS scores (r=0.52, p=0.003). Our findings suggest that quetiapine's antimanic and antidepressant efficacy in patients with rapid cycling bipolar disorder may potentially be related to decreased lactate levels in frontal regions of the brain.

Increased Low- and High-Frequency Oscillatory Activity in the Prefrontal Cortex of Fibromyalgia Patients.

Recent human neuroimaging studies have suggested that fibromyalgia (FM), a chronic widespread pain disorder, exhibits altered thalamic structure and function. Since the thalamus has extensive reciprocal connection with the cortex, structural and functional thalamic alterations in FM might be linked to aberrant thalamocortical oscillation. This study investigated the presence of abnormal brain rhythmicity in low- and high-frequency bands during resting state in patients with FM and their relationship to clinical pain symptom. Spontaneous magnetoencephalography (MEG) activity was recorded in 18 females with FM and 18 age- and sex-matched healthy control (HC) subjects. The most remarkable finding was that FM patients had general increases in theta, beta and gamma power along with a slowing of the dominant alpha peak. Increased spectral powers in the theta-band were primarily localized to the left dorsolateral prefrontal (DLPFC) and orbitofrontal cortex (OFC). Beta and gamma over-activation were localized to insular, primary motor and primary and secondary somatosensory (S2) cortices, as well as the DLPFC and OFC. Furthermore, enhanced high-frequency oscillatory activities in the DLPFC and OFC were associated with higher affective pain scores in patients with FM. Our results demonstrate that FM patients feature enhanced low- and high-frequency oscillatory activity in the brain areas related to cognitive and emotional modulation of pain. Increased low- and high-frequency activity of the prefrontal cortex may contribute to persistent perception of pain in FM. Therapeutic intervention based on manipulating neural oscillation to restore normal thalamocortical rhythmicity may be beneficial to pain relief in FM.

Impaired pre-attentive auditory processing in fibromyalgia: A mismatch negativity (MMN) study.

OBJECTIVE: Fibromyalgia (FM) patients often show deficits in cognitive functions such as attention and working memory. We assumed that pre-attentive information processing, a crucial element in human perception and cognition, would be altered in FM patients. Thus, the objective of this study was to determine whether FM patients exhibit alterations in pre-attentive processing as assessed by auditory mismatch negativity (MMN). METHODS: Auditory evoked magnetic fields were recorded in FM patients (n=18) and healthy control subjects (n=21) during a duration-deviant auditory oddball paradigm. The magnetic mismatch negativity (MMNm) was obtained by subtracting responses to standard tones from responses to deviant tones. Pressure pain thresholds over the thenar and trapezius muscles were determined using an algometer. RESULTS: MMNm peak amplitudes in right hemispheres were attenuated, and the directional asymmetry coefficient of the MMNm amplitude was lower in FM patients, indicating a more leftward asymmetry than in healthy control subjects. Smaller right MMNm amplitude was associated with lower pressure pain thresholds of thenar muscles in FM patients. CONCLUSIONS: Our results suggested that pre-attentive processing of auditory information is impaired in FM patients. SIGNIFICANCE: This study provided neurophysiological evidence of impaired pre-attentive sensory change detection in FM.

Disinhibition of the primary somatosensory cortex in patients with fibromyalgia.

Fibromyalgia (FM) is a chronic widespread pain condition linked to central sensitization. Altered excitability of sensorimotor cortex has been proposed as an underlying pathology of FM. This study aimed to investigate intracortical excitability of the primary somatosensory cortex (S1) and its potential role in clinical pain in patients with FM. Somatosensory evoked magnetic fields were recorded in 17 right-handed females with FM and 21 age-, sex-, and handedness-matched healthy control subjects. Paired-pulse median nerve stimulation was delivered to the left and right wrist. We assessed the peak-to-peak amplitudes of the N20m-P35m and peak amplitude of each N20m and P35m component. Paired-pulse suppression (PPS) of the second response was quantified as the ratio of the amplitudes of the second to the first response. Patients with FM displayed significantly higher PPS ratio for the N20m-P35m in both hemispheres, indicating reduced intracortical inhibition in the S1. Notably, PPS ratio for the P35m was higher in patients with FM than in healthy controls, whereas no differences were apparent in PPS ratio for the N20m in both hemispheres. For both the N20m-P35m and the P35m in the left hemisphere, PPS ratios were positively associated with the sensory pain on the short-form McGill Pain Questionnaire. This study demonstrated that intracortical inhibition in the S1 is compromised bilaterally in patients with FM, and the extent of disinhibition can be closely associated with increased clinical pain. Our results suggest that changes of intracortical inhibition of the S1 may contribute to the pathophysiology of FM pain.

Altered white matter integrity in the corpus callosum in fibromyalgia patients identified by tract-based spatial statistical analysis.

OBJECTIVE: Although recent imaging studies of fibromyalgia (FM) have converged on a dysfunction of central pain processing as the primary pathophysiologic cause of the disorder, microstructural changes of the white matter (WM) suggestive of abnormalities in the anatomic connectivity of the brain have not been extensively examined. The aim of this study was to investigate WM integrity and its possible relationship to pain symptoms in women with FM. METHODS: Nineteen FM patients and 21 age-, sex-, and education-matched healthy control subjects were included in the study and underwent diffusion-weighted imaging. Group differences in WM integrity, which were assessed via fractional anisotropy (FA), was investigated by applying tract-based spatial statistics. RESULTS: As compared with the healthy control group, the FM group showed a single cluster with lower FA in the left body of the corpus callosum, which was found to be connected to the bilateral sensorimotor cortices (P < 0.05, corrected for multiple comparisons). Furthermore, FA values in the cluster were negatively associated with sensory pain, as measured by the Short-Form McGill Pain Questionnaire, as well as with the relative magnitude of sensory pain versus affective pain (calculated by dividing the sensory score by the affective score). CONCLUSION: Findings of the current study demonstrated that patients with FM had disrupted WM microstructure in the body of the corpus callosum, which was associated with clinical pain intensity. Our results suggest that abnormal interhemispheric transfer might contribute to the heightened pain perception. Our findings further strengthen the hypothesis of centrally augmented pain processing in patients with FM.

Prefrontal cortical deficits in type 1 diabetes mellitus: brain correlates of comorbid depression.

CONTEXT Neural substrates that may be responsible for the high prevalence of depression in type 1 diabetes mellitus (T1DM) have not yet been elucidated. OBJECTIVE To investigate neuroanatomic correlates of depression in T1DM. DESIGN Case-control study using high-resolution brain magnetic resonance images. SETTINGS Joslin Diabetes Center and McLean Hospital, Massachusetts, and Seoul National University Hospital, South Korea. PARTICIPANTS A total of 125 patients with T1DM (44 subjects with ≥1 previous depressive episodes [T1DM-depression group] and 81 subjects who had never experienced depressive episodes [T1DM-only group]), 23 subjects without T1DM but with 1 or more previous depressive episodes (depression group), and 38 healthy subjects (control group). MAIN OUTCOME MEASURES Spatial distributions of cortical thickness for each diagnostic group were compared with the control group using a surface-based approach. Among patients with T1DM, associations between metabolic control measures and cortical thickness deficits were examined. RESULTS Thickness reduction in the bilateral superior prefrontal cortical regions was observed in the T1DM-depression, T1DM-only, and depression groups relative to the control group at corrected P < .01. Conjunction analyses demonstrated that thickness reductions related to the influence of T1DM and those related to past depressive episode influence were observed primarily in the superior prefrontal cortical region. Long-term glycemic control levels were associated with superior prefrontal cortical deficits in patients with T1DM (ß = -0.19, P = .02). CONCLUSIONS This study provides evidence that thickness reduction of prefrontal cortical regions in patients with T1DM, as modified by long-term glycemic control, could contribute to the increased risk for comorbid depression.

The neurobiological role of the dorsolateral prefrontal cortex in recovery from trauma. Longitudinal brain imaging study among survivors of the South Korean subway disaster.

CONTEXT: A multiwave longitudinal neuroimaging study in a cohort of direct survivors of a South Korean subway disaster, most of whom recovered from posttraumatic stress disorder 5 years after trauma, provided a unique opportunity to investigate the brain correlates of recovery from a severe psychological trauma. OBJECTIVES: To investigate region-specific brain mobilization during successful recovery from posttraumatic stress disorder by assessing cortical thickness multiple times from early after trauma to recovery, and to examine whether a brain-derived neurotrophic factor gene polymorphism was associated with this brain mobilization. DESIGN: Five-year follow-up case-control study conducted from 2003-2007. SETTING: Seoul National University and Hospital. PARTICIPANTS: Thirty psychologically traumatized disaster survivors and 36 age- and sex-matched control group members recruited from the disaster registry and local community, respectively, who contributed 156 high-resolution brain magnetic resonance images during 3 waves of assessments. MAIN OUTCOME MEASURES: Cerebral cortical thickness measured in high-resolution anatomic magnetic resonance images using a validated cortical thickness analysis tool and its prospective changes from early after trauma to recovery in trauma-exposed individuals and controls. RESULTS: Trauma-exposed individuals had greater dorsolateral prefrontal cortical (DLPFC) thickness 1.42 years after trauma (right DLPFC, 5.4%; left superior frontal cortex, 5.8%; and left inferior frontal cortex, 5.3% [all clusters, P ≤ .01]) relative to controls. Thicknesses gradually normalized over time during recovery. We found a positive linear trend, with trauma-exposed individuals with a valine/valine genotype having the greatest DLPFC cortical thickness, followed by those with a methionine genotype and controls (P < .001 for trend). Greater DLPFC thickness was associated with greater posttraumatic stress disorder symptom reductions and better recovery. CONCLUSION: The DLPFC region might play an important role in psychological recovery from a severely traumatic event in humans.

Laterobasal amygdalar enlargement in 6- to 7-year-old children with autism spectrum disorder.

CONTEXT: There is substantial imaging evidence for volumetric abnormalities of the amygdala in younger children with autism spectrum disorder (ASD). The amygdala can be divided into functionally distinct laterobasal, superficial, and centromedial subregions. To date, we are not aware of any in vivo reports specifically assessing subregional amygdalar abnormalities in individuals with ASD. OBJECTIVES: To evaluate alterations in subregional amygdalar morphology in children with ASD compared with typically developing (TD) children and to examine the relationships with ASD symptom severity. DESIGN: A cross-sectional study encompassing a narrow age range of children with ASD and age-matched TD children that evaluated magnetic resonance imaging-defined subregional morphology of the amygdala using a novel subregional analytic method. SETTING: Participants were recruited and clinically evaluated through the University of Washington Autism Center and imaged at the Diagnostic Imaging Sciences Center at the University of Washington. Imaging data were analyzed through the Brain Imaging Laboratory at the Seoul National University. PARTICIPANTS: Fifty-one children 6 to 7 years of age (ASD, n = 31 and TD, n = 20) were assessed using magnetic resonance imaging and behavioral measures. MAIN OUTCOME MEASURES: Volume and subregional measures of the amygdala and measures of social and communication functioning. RESULTS: The ASD group exhibited larger right and left amygdalae, by 12.7% and 11.0%, respectively, relative to the TD group. Subregional analysis revealed that the ASD group had enlarged laterobasal amygdalar subregions, relative to the TD group, after adjusting for age, sex, and hemispheric cerebral volume (P < .05, false discovery rate corrected and with clustered surface points >15). Exploratory analyses revealed that there were linear trends comparing a strictly defined subgroup of children with autistic disorder, who exhibited the greatest extent of laterobasal enlargement, followed by a subgroup of children with pervasive developmental disorder not otherwise specified and then the group of TD children (P for linear trend <.001). There were linear trends between enlargement of laterobasal subregions and lower levels of social and communication functioning (P < .001, P < .001, and P = .001 for 3 areas in the right laterobasal subregion; P < .001 for 1 area in the left laterobasal subregion). CONCLUSION: The current study demonstrates bilateral enlargement of laterobasal subregions of the amygdala in 6- to 7-year-old children with ASD and that subregional alterations are associated with deficits in social and communicative behavior.