Kirk M. Welker

Assessment of normal myelination with magnetic resonance imaging.

White matter myelination is essential to postnatal neurologic maturation and can be accurately evaluated by magnetic resonance imaging (MRI). Accordingly, MRI pulse sequences should be optimized for detection of myelin in young children. T1-weighted images are most useful during the first year of life. These demonstrate myelin-related white matter hyperintensity consequent to increasing cholesterol and galactocerebroside within myelin membranes. T2-weighted images are most useful in later stages of myelination, during which time elaboration of myelin leads to reduction in brain water content with associated T2 hypointensity. Additional information regarding the status of myelination can be obtained from T2-weighted fluid attenuation inversion recovery (FLAIR) and diffusion tensor imaging (DTI) pulse sequences. Clinically useful milestones for assessment of myelination across all these MRI pulse sequences are available as guidelines to image interpretation. Evaluation of myelination status using a combination of T1- and T2-weighted images should be routine in the interpretation of all pediatric brain MRI exams.

Deep brain stimulation induces BOLD activation in motor and non-motor networks: an fMRI comparison study of STN and EN/GPi DBS in large animals.

The combination of deep brain stimulation (DBS) and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. The goal of this study was to trace DBS-induced global neuronal network activation in a large animal model by monitoring the blood oxygenation level-dependent (BOLD) response on fMRI. We conducted DBS in normal anesthetized pigs, targeting the subthalamic nucleus (STN) (n=7) and the entopeduncular nucleus (EN), the non-primate analog of the primate globus pallidus interna (n=4). Using a normalized functional activation map for group analysis and the application of general linear modeling across subjects, we found that both STN and EN/GPi DBS significantly increased BOLD activation in the ipsilateral sensorimotor network (FDR<0.001). In addition, we found differential, target-specific, non-motor network effects. In each group the activated brain areas showed a distinctive correlation pattern forming a group of network connections. Results suggest that the scope of DBS extends beyond an ablation-like effect and that it may have modulatory effects not only on circuits that facilitate motor function but also on those involved in higher cognitive and emotional processing. Taken together, our results show that the swine model for DBS fMRI, which conforms to human implanted DBS electrode configurations and human neuroanatomy, may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS.

Arrested Pneumatization of the Skull Base: Imaging Characteristics

OBJECTIVE Arrested skull base pneumatization is a benign developmental variant that can be confused with significant skull base disease processes. This study reviews the imaging findings in 30 suspected cases of arrested skull base pneumatization. CONCLUSION When encountering a nonexpansile lesion with osteosclerotic borders, internal fat, and curvilinear calcifications in the basisphenoid bone or adjacent skull base, radiologists should strongly consider the diagnosis of arrested pneumatization.

Default Mode Network Disruption Secondary to a Lesion in the Anterior Thalamus

OBJECTIVE To describe the neuroanatomical correlations of an isolated lesion in the anterior thalamus using functional imaging in a 40-year-old man with multiple sclerosis. DESIGN Case report with 10 cognitively normal controls. SETTING Mayo Clinic, Rochester, Minnesota. PATIENT A 40-year-old man with a 2-week course of acute-onset amnesia, abulia, poor concentration, hypersomnolence, and reclusiveness. INTERVENTION Functional magnetic resonance imaging. RESULTS Magnetic resonance imaging demonstrated a large gadolinium-enhancing plaque in the left anterior thalamus and other demyelinating plaques in the subcortical and periventricular white matter, consistent with the diagnosis of multiple sclerosis. His symptoms persisted at the 7-month follow-up. The patients resting state functional magnetic resonance image demonstrated an asymmetric disruption of the posterior cingulate portion of the default mode network ipsilateral to the left thalamic lesion. CONCLUSIONS A large multiple sclerosis plaque in the deep gray matter altered the resting state functional connectivity in a patient presenting with pure cognitive dysfunction. Such altered connectivity may underlie cognitive symptoms in neurologic disease. In addition, this case provides lesional evidence of default mode network circuitry involving the pathways of the circuit of Papez.

Motor and Nonmotor Circuitry Activation Induced by Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease: Intraoperative Functional Magnetic Resonance Imaging for Deep Brain Stimulation.

OBJECTIVE To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease would affect the activity of motor and nonmotor networks, we applied intraoperative functional magnetic resonance imaging (fMRI) to patients receiving DBS. PATIENTS AND METHODS Ten patients receiving STN DBS for Parkinson disease underwent intraoperative 1.5-T fMRI during high-frequency stimulation delivered via an external pulse generator. The study was conducted between January 1, 2013, and September 30, 2014. RESULTS We observed blood oxygen level-dependent (BOLD) signal changes (false discovery rate <0.001) in the motor circuitry (including the primary motor, premotor, and supplementary motor cortices; thalamus; pedunculopontine nucleus; and cerebellum) and in the limbic circuitry (including the cingulate and insular cortices). Activation of the motor network was observed also after applying a Bonferroni correction (P<.001) to the data set, suggesting that across patients, BOLD changes in the motor circuitry are more consistent compared with those occurring in the nonmotor network. CONCLUSION These findings support the modulatory role of STN DBS on the activity of motor and nonmotor networks and suggest complex mechanisms as the basis of the efficacy of this treatment modality. Furthermore, these results suggest that across patients, BOLD changes in the motor circuitry are more consistent than those in the nonmotor network. With further studies combining the use of real-time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01809613.

Effect of Left Atrial Ablation Process and Strategy on Microemboli Formation During Irrigated Radiofrequency Catheter Ablation in an In Vivo Model

Background—Formation of microemboli during catheter ablation has been suggested as a cause for asymptomatic cerebral emboli. However, it is unknown which part of the process and ablation setting/strategy is most strongly related to this occurrence. Methods and Results—A total of 27 pigs were used. Catheter/sheath manipulations in left atrium were performed in 25 of 27 pigs outfitted with microemboli monitoring systems. Ablations using open-irrigated radiofrequency catheters were performed in 18 of 25 pigs. Two of 27 pigs did not undergo left atrial procedures and were injected with microembolic materials in the carotid artery to serve as positive controls. In total, 334 sheath/catheter manipulations (transseptal puncture, sheath flushing, catheter insertion, pulmonary vein venography, and sheath exchange) and 333 radiofrequency applications (power setting, 30/50 W; point-by-point/drag ablations) were analyzed. High microbubble volume in the extracorporeal circulation loop and a high number of microembolic signals in carotid artery were observed during sheath/catheter manipulations especially in saline/contrast injections at fast speed and ablations with steam pop. Fast sheath flushing produced significantly higher microbubble volume than slow sheath flushing (median, 12 200 versus 121 nL; P<0.0001). A total of 44 of 126 (35%) blood filters in the circulation loop showed microparticles (thrombus/coagulum and tissue). Most of them were seen after radiofrequency application especially in 50-W ablations, drag ablations, and steam pop. Brain magnetic resonance imaging showed positive-embolic lesions in control pigs. Conclusions—Formation of microbubbles was the greatest during fast saline/contrast injections and steam pops, whereas high-power radiofrequency applications, drag ablations, and steam pops produced most of the microparticles.

Lateralization and localization of epilepsy related hemodynamic foci using presurgical fMRI

OBJECTIVE The aim was to develop a method for the purpose of localizing epilepsy related hemodynamic foci for patients suffering intractable focal epilepsy using task-free fMRI alone. METHODS We studied three groups of subjects: patients with intractable focal epilepsy, healthy volunteers performing motor tasks, and healthy volunteers in resting state. We performed spatial independent component analysis (ICA) on the fMRI alone data and developed a set of IC selection criteria to identify epilepsy related ICs. The method was then tested in the two healthy groups. RESULTS In seven out of the nine surgery patients, identified ICs were concordant with surgical resection. Our results were also consistent with presurgical evaluation of the remaining one patient without surgery and may explain why she was not suitable for resection treatment. In the motor task study of ten healthy subjects, our method revealed components with concordant spatial and temporal features as expected from the unilateral motor tasks. In the resting state study of seven healthy subjects, the method successfully rejected all components in four out of seven subjects as non-epilepsy related components. CONCLUSION These results suggest the lateralization and localization value of fMRI alone in presurgical evaluation for patients with intractable unilateral focal epilepsy. SIGNIFICANCE The proposed method is noninvasive in nature and easy to implement. It has the potential to be incorporated in current presurgical workup for treating intractable focal epilepsy patients.

Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal.

The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; ≥15 headache days/month) to episodic (EM; <15 headache days/month) migraine following prophylactic treatment with onabotulinumtoxinA (BoNT-A). Specifically, we examined whether CM patients responsive to prophylaxis (responders; n = 11), as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and <15 headache days/month), compared to CM patients whose migraine frequency remained unchanged (non-responders; n = 12), showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC) using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports of headache frequency over the 4 weeks prior to (pre-treatment) and following (post-treatment) prophylaxis were compared (post minus pre) and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within 2 weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI) and anterior insula (aINS), and left superior temporal gyrus (STG) and pars opercularis (ParsOp) compared to non-responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI) that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC) and dorsomedial prefrontal cortices (DMPFC) in responders, whereas non-responders showed increased connectivity between the ParsOp seed and LOC. Overall, our findings revealed distinct morphometric and functional brain changes in CM patients that reverted to EM following prophylactic treatment compared to CM patients that showed no change in disease status. Elucidating the CNS changes involved in disease reversal may be critical to discovering interventions that prevent or slow the progression of CM. Such changes may aid in the evaluation of treatments as well as provide markers for disease “de-chronification”.

Characterization of multiple sclerosis plaques using susceptibility-weighted imaging at 1.5 T: can perivenular localization improve specificity of imaging criteria?

Background and Purpose The purpose of this study was to determine if magnetic resonance (MR) susceptibility-weighted imaging (SWI) can increase the conspicuity of corticomedullary veins within the white matter lesions of multiple sclerosis (MS) and, thus, aid in distinguishing plaques from leukoaraiosis. Methods We retrospectively reviewed MR examinations in 21 patients with a clinical diagnosis of MS and 18 patients with a clinical diagnosis of dementia. Examinations included fluid-attenuated inversion recovery (FLAIR) and SWI sequences obtained in the axial plane. Lesions greater than 5 mm in diameter on the axial FLAIR sequence were identified as periventricular or subcortical. Three neuroradiologists evaluated SWI images, compared with FLAIR, for a centrally located signal void in each lesion that was scored as present, absent, or indeterminate. Results In patients with MS, central veins were present in both periventricular lesions (75%, P < 0.001) and subcortical lesions (52%, P < 0.005). In patients with dementia, central veins were seen much less frequently in subcortical lesions (14%, P < 0.001); their association with periventricular lesions was not significant. Conclusions Central veins were detected in MS lesions with a significantly greater frequency than that in patients with dementia. Susceptibility-weighted imaging increases the conspicuity of corticomedullary veins and may improve the specificity of MR findings in MS.

The Impact of Mirth-Inducing Ventral Striatal Deep Brain Stimulation on Functional and Effective Connectivity

Abstract Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is an investigational therapy for treatment‐resistant obsessive‐compulsive disorder. The ability of VC/VS DBS to evoke spontaneous mirth in patients, often accompanied by smiling and laughter, is clinically well documented. However, the neural correlates of DBS‐evoked mirth remain poorly characterized. Patients undergoing VC/VS DBS surgery underwent intraoperative evaluation in which mirth‐inducing and non‐mirth‐inducing stimulation localizations were identified. Using dynamic causal modeling (DCM) for fMRI, the effect of mirth‐inducing DBS on functional and effective connectivity among established nodes in limbic cortico‐striato‐thalamo‐cortical (CSTC) circuitry was investigated. Both mirth‐inducing and non‐mirth‐inducing VC/VS DBS consistently resulted (conjunction, global null, family‐wise error‐corrected P < 0.05) in activation of amygdala, ventral striatum, and mediodorsal thalamus. However, only mirth‐inducing DBS resulted in functional inhibition of anterior cingulate cortex. Dynamic causal modeling revealed that mirth‐inducing DBS enhanced effective connectivity from anterior cingulate to ventral striatum, while attenuating connectivity from thalamus to ventral striatum relative to non‐mirth‐inducing stimulation. These results suggest that DBS‐evoked mood elevation is accompanied by distinct patterns of limbic thalamocortical connectivity. Using the novel combination of DBS‐evoked mood alteration and functional MRI in human subjects, we provide new insights into the network‐level mechanisms that influence affect.