Crystal Franklin

Fronto-limbic circuitry in euthymic bipolar disorder: Evidence for prefrontal hyperactivation

Functional magnetic resonance imaging (fMRI) studies of bipolar disorder have revealed fronto-limbic abnormalities in patients during manic and depressive episodes. However, relatively few studies have examined neural activity during euthymia, leaving unanswered questions concerning the impact of mood state on activity in these brain regions. In the present study, we examined 15 remitted bipolar type I patients and 16 demographically matched healthy comparison subjects during performance on an affective face-matching task previously shown to elicit amygdala hyperactivation and prefrontal hypoactivation in manic relative to healthy subjects. In our euthymic sample, amygdala activation did not differ from controls. However, bipolar patients showed hyperactivation in inferior prefrontal cortical regions compared with controls, a finding that contrasts with the hypoactivation previously reported in this region in manic patients. Given the reciprocal relationship between the prefrontal cortex and limbic structures, we propose state-related amygdala activity, similar to that of healthy controls, may be associated with prefrontal hyperactivation when bipolar patients are asymptomatic.

Brain magnetic resonance imaging in newly diagnosed systemic lupus erythematosus

Objective We wished to determine the prevalence of cerebral atrophy and focal lesions in a cohort of patients with newly diagnosed systemic lupus erythematosus (SLE) and the association of these brain abnormalities with clinical characteristics. Methods A total of 97 patients with SLE, within 9 months of diagnosis, with 4 or more American College of Rheumatology classification criteria, were enrolled. Brain magnetic resonance imaging was performed. Results The patients were 97% female, mean age 38.1 (SD 12.2) years, education 15.1 (2.8) years; 59 Caucasian, 11 African American, 19 Hispanic, 5 Asian, and 3 other ethnicity. Cerebral atrophy was prevalent in 18% (95% CI 11%–27%): mild in 12%, moderate in 5%. Focal lesions were prevalent in 8% (95% CI 4%–16%): mild in 2%, moderate in 5%, severe in 1%. Patients with cerebral atrophy were more likely to have anxiety disorder (p = 0.04). Patients with focal lesions were more likely to be African American (p = 0.045) and had higher Safety of Estrogens in Lupus Erythematosus National Assessment SLEDAI scores (p = 0.02) and anti-dsDNA (p = 0.05). Conclusion In this population with newly diagnosed SLE, brain abnormalities were prevalent in 25% of patients. These findings suggest that the brain may be affected extremely early in the course of SLE, even before the clinical diagnosis of SLE is made. Followup of these patients is planned, to determine the reversibility or progression of these abnormalities and their association with and potential predictive value for subsequent neuropsychiatric SLE manifestations.

Neural Correlates of Efficacy of Voice Therapy in Parkinson’s Disease Identified by Performance–Correlation Analysis

LSVT® LOUD (Lee Silverman Voice Treatment) is efficacious in the treatment of speech disorders in idiopathic Parkinsons disease (IPD), particularly hypophonia. Functional imaging in patients with IPD has shown abnormalities in several speech regions and changes in these areas immediately following treatment. This study serves to extend the analysis by correlating changes of regional neural activity with the main behavioral change following treatment, namely, increased vocal intensity. Ten IPD participants with hypophonia were studied before and after LSVT LOUD. Cerebral blood flow during rest and reading conditions were measured by H215O‐positron emission tomography. Z‐score images were generated by contrasting reading with rest conditions for pre‐ and post‐LSVT LOUD sessions. Neuronal activity during reading in the pre‐ versus post‐LSVT LOUD contrast was correlated with corresponding change in vocal intensity to generate correlation images. Behaviorally, vocal intensity for speech tasks increased significantly after LSVT LOUD. The contrast and correlation analyses indicate a treatment‐dependent shift to the right hemisphere with modification in the speech motor regions as well as in prefrontal and temporal areas. We interpret the modification of activity in these regions to be a top–down effect of LSVT LOUD. The absence of an effect of LSVT LOUD on the basal ganglion supports this argument. Our findings indicate that the therapeutic effect of LSVT LOUD in IPD hypophonia results from a shift in cortical activity to the right hemisphere. These findings demonstrate that the short‐term changes in the speech motor and multimodal integration areas can occur in a top–down manner. Hum Brain Mapp, 2010.

Modeling motor connectivity using TMS/PET and structural equation modeling

Structural equation modeling (SEM) was applied to positron emission tomographic (PET) images acquired during transcranial magnetic stimulation (TMS) of the primary motor cortex (M1(hand)). TMS was applied across a range of intensities, and responses both at the stimulation site and remotely connected brain regions covaried with stimulus intensity. Regions of interest (ROIs) were identified through an activation likelihood estimation (ALE) meta-analysis of TMS studies. That these ROIs represented the network engaged by motor planning and execution was confirmed by an ALE meta-analysis of finger movement studies. Rather than postulate connections in the form of an a priori model (confirmatory approach), effective connectivity models were developed using a model-generating strategy based on improving tentatively specified models. This strategy exploited the experimentally imposed causal relations: (1) that response variations were caused by stimulation variations, (2) that stimulation was unidirectionally applied to the M1(hand) region, and (3) that remote effects must be caused, either directly or indirectly, by the M1(hand) excitation. The path model thus derived exhibited an exceptional level of goodness (chi(2)=22.150, df=38, P=0.981, TLI=1.0). The regions and connections derived were in good agreement with the known anatomy of the human and primate motor system. The model-generating SEM strategy thus proved highly effective and successfully identified a complex set of causal relationships of motor connectivity.

Electrophysiological and functional connectivity of the human supplementary motor area

Neuro-imaging methods for detecting functional and structural inter-regional connectivity are in a rapid phase of development. While reports of regional connectivity patterns based on individual methods are becoming common, studies comparing the results of two or more connectivity-mapping methods remain rare. In this study, we applied transcranial magnetic stimulation during PET imaging (TMS/PET), a stimulation-based method, and meta-analytic connectivity modeling (MACM), a task-based method to map the connectivity patterns of the supplementary motor area (SMA). Further, we drew upon the behavioral domain meta-data of the BrainMap® database to characterize the behavioral domain specificity of two maps. Both MACM and TMS/PET detected multi-synaptic connectivity patterns, with the MACM-detected connections being more extensive. Both MACM and TMS/PET detected connections belonging to multiple behavioral domains, including action, cognition and perception. Finally, we show that the two connectivity-mapping methods are complementary in that, the MACM informed on the functional nature of SMA connections, while TMS/PET identified brain areas electrophysiologically connected with the SMA. Thus, we demonstrate that integrating multimodal database and imaging techniques can derive comprehensive connectivity maps of brain areas.

Neuroimaging evidence of white matter inflammation in newly diagnosed Systemic Lupus Erythematosus

OBJECTIVE Central nervous system (CNS) involvement occurs frequently in systemic lupus erythematosus (SLE) and frequently results in morbidity. The primary pathophysiology of CNS involvement in SLE is thought to be inflammation secondary to autoantibody-mediated vasculitis. Neuroimaging studies have shown hypometabolism (representing impending cell failure) and atrophy (representing late-stage pathology), but not inflammation. The purpose of this study was to detect the presence and regional distribution of inflammation (hypermetabolism) and tissue failure, apoptosis, or atrophy (hypometabolism). METHODS Eighty-five patients with newly diagnosed SLE, who had no focal neurologic symptoms, were studied. Disease activity was quantified using the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI), a validated index of SLE-related disease activity. 18Fluorodeoxyglucose (FDG) positron emission tomography (PET) images of glucose uptake were analyzed by visual inspection and as group statistical parametric images, using the SELENA-SLEDAI score as the analysis regressor. RESULTS SELENA-SLEDAI-correlated increases in glucose uptake were found throughout the white matter, most markedly in heavily myelinated tracts. SELENA-SLEDAI-correlated decreases were found in the frontal and parietal cortex, in a pattern similar to that seen during visual inspection and presented in previous reports of hypometabolism. CONCLUSION The SELENA-SLEDAI-correlated increases in glucose consumption are potential evidence of inflammation, consistent with prior reports of hypermetabolism in inflammatory disorders. To our knowledge, this is the first imaging-based evidence of SLE-induced CNS inflammation in an SLE inception cohort. The dissociation among 18FDG uptake characteristics, spatial distribution, and disease activity correlation is in accordance with the notion that glucose hypermetabolism and hypometabolism reflect fundamentally different aspects of the pathophysiology of SLE with CNS involvement.

PET imaging in the photosensitive baboon : Case-controlled study

Summary:  Purpose: The baboon (Papio hamadryas spp) offers a natural primate animal model of photosensitive generalized epilepsy. This study compared changes in cerebral blood flow (CBF) during intermittent light stimulation (ILS) between photosensitive and asymptomatic baboons.

Concurrent TMS to the primary motor cortex augments slow motor learning

Transcranial magnetic stimulation (TMS) has shown promise as a treatment tool, with one FDA approved use. While TMS alone is able to up- (or down-) regulate a targeted neural system, we argue that TMS applied as an adjuvant is more effective for repetitive physical, behavioral and cognitive therapies, that is, therapies which are designed to alter the network properties of neural systems through Hebbian learning. We tested this hypothesis in the context of a slow motor learning paradigm. Healthy right-handed individuals were assigned to receive 5 Hz TMS (TMS group) or sham TMS (sham group) to the right primary motor cortex (M1) as they performed daily motor practice of a digit sequence task with their non-dominant hand for 4 weeks. Resting cerebral blood flow (CBF) was measured by H2(15)O PET at baseline and after 4 weeks of practice. Sequence performance was measured daily as the number of correct sequences performed, and modeled using a hyperbolic function. Sequence performance increased significantly at 4 weeks relative to baseline in both groups. The TMS group had a significant additional improvement in performance, specifically, in the rate of skill acquisition. In both groups, an improvement in sequence timing and transfer of skills to non-trained motor domains was also found. Compared to the sham group, the TMS group demonstrated increases in resting CBF specifically in regions known to mediate skill learning namely, the M1, cingulate cortex, putamen, hippocampus, and cerebellum. These results indicate that TMS applied concomitantly augments behavioral effects of motor practice, with corresponding neural plasticity in motor sequence learning network. These findings are the first demonstration of the behavioral and neural enhancing effects of TMS on slow motor practice and have direct application in neurorehabilitation where TMS could be applied in conjunction with physical therapy.

Intrinsic Resting-State Functional Connectivity in the Human Spinal Cord at 3.0 T

PURPOSE To apply resting-state functional magnetic resonance (MR) imaging to map functional connectivity of the human spinal cord. MATERIALS AND METHODS Studies were performed in nine self-declared healthy volunteers with informed consent and institutional review board approval. Resting-state functional MR imaging was performed to map functional connectivity of the human cervical spinal cord from C1 to C4 at 1 × 1 × 3-mm resolution with a 3.0-T clinical MR imaging unit. Independent component analysis (ICA) was performed to derive resting-state functional MR imaging z-score maps rendered on two-dimensional and three-dimensional images. Seed-based analysis was performed for cross validation with ICA networks by using Pearson correlation. RESULTS Reproducibility analysis of resting-state functional MR imaging maps from four repeated trials in a single participant yielded a mean z score of 6 ± 1 (P < .0001). The centroid coordinates across the four trials deviated by 2 in-plane voxels ± 2 mm (standard deviation) and up to one adjacent image section ± 3 mm. ICA of group resting-state functional MR imaging data revealed prominent functional connectivity patterns within the spinal cord gray matter. There were statistically significant (z score > 3, P < .001) bilateral, unilateral, and intersegmental correlations in the ventral horns, dorsal horns, and central spinal cord gray matter. Three-dimensional surface rendering provided visualization of these components along the length of the spinal cord. Seed-based analysis showed that many ICA components exhibited strong and significant (P < .05) correlations, corroborating the ICA results. Resting-state functional MR imaging connectivity networks are qualitatively consistent with known neuroanatomic and functional structures in the spinal cord. CONCLUSION Resting-state functional MR imaging of the human cervical spinal cord with a 3.0-T clinical MR imaging unit and standard MR imaging protocols and hardware reveals prominent functional connectivity patterns within the spinal cord gray matter, consistent with known functional and anatomic layouts of the spinal cord.

Aging interferes central control mechanism for eccentric muscle contraction

Previous studies report greater activation in the cortical motor network in controlling eccentric contraction (EC) than concentric contraction (CC) despite lower muscle activation level associated with EC vs. CC in healthy, young individuals. It is unknown, however, whether elderly people exhibiting increased difficulties in performing EC than CC possess this unique cortical control mechanism for EC movements. To address this question, we examined functional magnetic resonance imaging (fMRI) data acquired during EC and CC of the first dorsal interosseous (FDI) muscle in 11 young (20–32 years) and 9 old (67–73 years) individuals. During the fMRI experiment, all subjects performed 20 CC and 20 EC of the right FDI with the same angular distance and velocity. The major findings from the behavioral and fMRI data analysis were that (1) movement stability was poorer in EC than CC in the old but not the young group; (2) similar to previous electrophysiological and fMRI reports, the EC resulted in significantly stronger activation in the motor control network consisting of primary, secondary and association motor cortices than CC in the young and old groups; (3) the biased stronger activation towards EC was significantly greater in the old than the young group especially in the secondary and association cortices such as supplementary and premotor motor areas and anterior cingulate cortex; and (4) in the primary motor and sensory cortices, the biased activation towards EC was significantly greater in the young than the old group. Greater activation in higher-order cortical fields for controlling EC movement by elderly adults may reflect activities in these regions to compensate for aging-related impairments in the ability to control complex EC movements. Our finding is useful for potentially guiding the development of targeted therapies to counteract age-related movement deficits and to prevent injury.