Catherine S. Hubbard

Substantial clinical heterogeneity and comorbidity inherent amongst mental disorders limit the identification of neuroimaging biomarkers that can reliably track clinical symptoms. Strategies that enable generation of meaningful and replicable neurobiological markers at the individual level will push the field of neuropsychiatry forward in developing efficacious personalized treatment. The current study included 142 adult patients with a primary diagnosis of schizophrenia (SCZ), bipolar (BP), or attention deficit/hyperactivity disorder (ADHD), and 67 patient ratings across four behavioral measures. Using functional connectivity derived from a personalized fMRI approach, we identified several candidate imaging markers related to dimensional phenotypes across disorders, assessed the internal and external generalizability of these markers, and compared the probability of replicating findings across datasets using individual and group-averaged defined functional regions. We identified subject-specific connections related to three different clinical domains (attention deficit, appetite-energy, psychosis-positive) in a discovery dataset. Importantly, these connectivity biomarkers were robust and were reproduced in an independent validation dataset. For markers related to neurovegetative symptoms (attention deficit, appetite-energy symptoms), the brain connections involved showed similar connectivity patterns across the different diagnoses. However, psychosis-positive symptoms were associated with connections of varying strength across disorders. Finally, we found that markers for symptom domains were replicable for individually-specified connections, but not for group template-derived connections. Our personalized strategies allowed us to identify meaningful and generalizable imaging markers for symptom domains in patients who exhibit high levels of heterogeneity. These biomarkers may shed new light on the connectivity underpinnings of psychiatric symptoms and lead to personalized interventions.

Alterations in fractional anisotropy (FA) have been considered to reflect microstructural white matter (WM) changes in disease conditions; however, no study to date has examined WM changes using diffusion tensor imaging (DTI) in adolescents with irritable bowel syndrome (IBS). The objective of the present study was two-fold: (1) to determine whether differences in FA, and other non-FA metrics, were present in adolescents with IBS compared to healthy controls using whole-brain, region of interest (ROI)-restricted tract-based spatial statistics (TBSS) and canonical ROI DTI analyses for the cingulum bundle, and (2) to determine whether these metrics were related to clinical measures of disease duration and pain intensity in the IBS group. A total of 16 adolescents with a Rome III diagnosis of IBS (females = 12; mean age = 16.29, age range: 11.96–18.5 years) and 16 age- and gender-matched healthy controls (females = 12; mean age = 16.24; age range: 11.71–20.32 years) participated in this study. Diffusion-weighted images were acquired using a Siemens 3-T Trio Tim Syngo MRI scanner with a 32-channel head coil. The ROI-restricted TBSS and canonical ROI-based DTI analyses revealed that adolescents with IBS showed decreased FA in the right dorsal cingulum bundle compared to controls. No relationship between FA and disease severity measures was found. Microstructural WM alterations in the right dorsal cingulum bundle in adolescents with IBS may reflect a premorbid brain state or the emergence of a disease-driven process that results from complex changes in pain- and affect-related processing via spinothalamic and corticolimbic pathways.

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder of unknown etiology. Although relatively common in children, how this condition affects brain structure and function in a pediatric population remains unclear. Here, we investigate brain changes in adolescents with IBS and healthy controls. Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution T1-weighted anatomical scan was acquired followed by a T2-weighted functional scan. We used a surface-based morphometric approach along with a seed-based resting-state functional connectivity (RS-FC) analysis to determine if groups differed in cortical thickness and whether areas showing structural differences also showed abnormal RS-FC patterns. Patients completed the Abdominal Pain Index and the GI Module of the Pediatric Quality of Life Inventory to assess abdominal pain severity and impact of GI symptoms on health-related quality of life (HRQOL). Disease duration and pain intensity were also assessed. Pediatric IBS patients, relative to controls, showed cortical thickening in the posterior cingulate (PCC), whereas cortical thinning in posterior parietal and prefrontal areas were found, including the dorsolateral prefrontal cortex (DLPFC). In patients, abdominal pain severity was related to cortical thickening in the intra-abdominal area of the primary somatosensory cortex (SI), whereas HRQOL was associated with insular cortical thinning. Disease severity measures correlated with cortical thickness in bilateral DLPFC and orbitofrontal cortex. Patients also showed reduced anti-correlations between PCC and DLPFC compared to controls, a finding that may reflect aberrant connectivity between default mode and cognitive control networks. We are the first to demonstrate concomitant structural and functional brain changes associated with abdominal pain severity, HRQOL related to GI-specific symptoms, and disease-specific measures in adolescents with IBS. It is possible such changes will be responsive to therapeutic intervention and may be useful as potential markers of disease progression or reversal.

Background: Increased attention to gastrointestinal (GI) symptoms and disease‐specific contexts may play an important role in the enhanced perception of visceral stimuli frequently reported in patients with irritable bowel syndrome (IBS). In this study, we test the hypothesis that altered attentional mechanisms underlie central pain amplification in IBS.Methods: To evaluate brain networks that support alerting, orienting, and executive attention, we employed the attention network test (ANT), a modified flanker task which measures the efficiency of functioning of core attentional networks, during functional magnetic resonance imaging in 15 IBS patients (mean age = 31 [11.96]) and 14 healthy controls (HCs; mean age = 31 [10.91]).Key Results: Patients with IBS, compared to HCs, showed shorter reaction times during the alerting and orienting conditions which were associated with greater activation of anterior midcingulate and insular cortices, and decreased activity in the right inferior frontal junction and supplementary motor cortex. Patients also showed activation in the dorsal medial prefrontal cortex and concurrent thalamic deactivation during the executive control portion of the ANT relative to HCs, but no group difference in reaction times were found. The activity in brain regions showing group differences during the ANT were associated with measures of GI‐specific anxiety, pain catastrophizing, and fear of uncertainty. In IBS, activity in the anterior midcingulate during alerting correlated with duration of GI‐symptoms and overall symptom severity.Conclusions & Inferences: Together, these results suggest that IBS patients have specific abnormalities in attentional network functioning and these deficits may underlie symptom‐related anxiety, hypervigilance, and visceral hypersensitivity.

To investigate the neuroanatomical and functional brain changes in migraine patients relative to healthy controls, we used a combined analytical approach including voxel- and surface-based morphometry along with resting-state functional connectivity to determine whether areas showing structural alterations in patients also showed abnormal functional connectivity. Additionally, we wanted to assess whether these structural and functional changes were associated with group differences in pain catastrophizing and migraine-related disease variables in patients. We acquired T1-weighted anatomical and functional magnetic resonance imaging scans during rest in human subjects with a diagnosis of migraine and healthy controls. Structural analyses revealed greater left hippocampal gray matter volume and reduced cortical thickness in the left anterior midcingulate in patients compared with controls. We also observed negative associations between pain catastrophizing and migraine disease variables and gray matter in areas implicated in processing the sensory, affective, and cognitive aspects of pain in patients. Functional connectivity analyses showed that migraine patients displayed disrupted connectivity between default mode, salience, cognitive, visuospatial, and sensorimotor networks, which was associated with group differences in pain catastrophizing and migraine-related disease variables in patients. Together, our findings show widespread morphological and functional brain abnormalities in migraineurs in affective, cognitive, visual, and pain-related brain areas, which are associated with increased pain catastrophizing, disease chronicity, and severity of symptoms, suggesting that these structural and functional changes may be a consequence of repeated, long-term nociceptive signaling leading to increased pain sensitivity, mood disturbances, and maladaptive coping strategies to deal with unrelenting pain.