Aberrant emotional processing in posterior cortical midline structures in bipolar II depression.

Bipolar II depression is a serious and disabling illness associated with significant impairment and high rates of suicide attempts. However, mechanisms underlying emotional dysregulation in this condition are poorly characterized. The goal of this work was to investigate one component of emotional processing in this disorder, brain activation associated with exposure to emotional faces. Functional MRI was used to study 16 unmedicated male subjects with bipolar II depression and 19 healthy male controls. The activation paradigm exposed subjects to happy, fearful and neutral faces. The two key findings of this study were as follows. First, bipolar subjects demonstrated significantly decreased activation in response to happy facial expression in the left posterior cortical midline structures (CMS) and frontal cortex. Second, depression severity was positively correlated with activation of the posterior CMS and other regions. Our results suggest that mechanisms involving CMS dysfunction may play a role in the neurobiology of bipolar II depression as has been demonstrated for unipolar illness. Further investigations of CMS function in bipolar spectrum disorders are warranted.

Striatal and cortical midline activation and connectivity associated with suicidal ideation and depression in bipolar II disorder.

BACKGROUND: Considerable evidence implicates dysfunction of striatal and cortical midline structure (CMS) circuitry in mood disorders. Whether such aberrations exist in bipolar II depression is unknown. METHODS: Sixteen unmedicated subjects with bipolar II depression and 19 healthy controls were studied using functional MRI and a motor activation paradigm. Analyses of both activation and functional connectivity were conducted. RESULTS: A history of suicidal ideation (SI) was negatively correlated with activation of the left putamen while depression severity was positively correlated with activation of the left thalamus. The superior bilateral putamen was simultaneously correlated with depression severity and anti-correlated with SI. Striatal functional connectivity was altered with the bilateral CMS and right inferior parietal lobule. Depression severity was correlated with strength of connectivity between the bilateral striatum and the right lingual gyrus and left cerebellum. LIMITATIONS: Only males experiencing an episode of major depression were studied. CONCLUSIONS: Striatal and CMS circuit abnormalities likely contribute to the neurobiology of bipolar II depression. Altered connectivity of the striatum may directly impact depression severity. Further, dissociable components of activation associated with depression severity and suicidal ideation may exist. Finally, the motor activation paradigm used in this study appears to be a useful probe of some neural processes underlying bipolar II depression.

Reliability of fMRI motor tasks in structures of the corticostriatal circuitry: implications for future studies and circuit function.

The corticostriatal circuits are important information processing networks. There is evidence that these circuits may be dysfunctional in a variety of neuropsychiatric conditions ranging from Parkinson's disease to bipolar disorder. Cross-sectional fMRI studies may clarify normal circuit function, and longitudinal studies may provide information on changes related to age in control subjects, as well as illness progression and treatment response in patient groups. In this paper, we report a comprehensive analysis of the utility of several motor tasks as cross-sectional and longitudinal probes of corticostriatal function in terms of their activation strength and reliability. Our findings suggest that the motor tasks studied can be useful probes of corticostriatal function for studies utilizing group comparisons. However, longitudinal clinical studies in which individual results are important will need to take into account wide variation in individual activation and reliability. For example, measures of activation strength and reliability based on percent signal change display a dichotomy between simple motor tasks, which have high reliability and low activation, and complex tasks, which have lower reliability and higher activation. Size and overlap ratios calculated from activation maps produced a different view of reliability than intraclass correlation coefficients (ICC) based on percent signal change. Finally, these results suggest that the corticostriatal circuitry exhibit individualized responses to motor adaptation.

Enhanced delivery of naked DNA to the skin by non-invasive in vivo electroporation.

DNA delivery to skin may be useful for the treatment of skin diseases, DNA vaccinations, and other gene therapy applications requiring local or systemic distribution of a transgene product. However, the effective, consistent and patient-friendly transfection of skin cells remains a challenge. In a mouse model, we evaluated the effectiveness of intradermal injection of plasmid DNA followed by noninvasive in vivo electroporation (EP) as a method to improve transfection in skin. We achieved a several hundred-fold stimulation of gene expression by EP, sufficient to produce clinically relevant amounts of transgene product. We studied the effect of DNA dose and time after treatment as well as various EP pulse parameters on the efficiency of gene expression. EP under conditions of constant charge transfer revealed that the applied voltage was the main determinant for transgene expression efficiency while other pulse parameters had lesser effects. Patient-friendly, noninvasive meander electrodes which we designed for clinical applications proved equally effective and safe as plate electrodes. We also showed for the first time that noninvasive EP is effective in stimulating transfection and gene expression in human skin, particularly in the epidermis. Our findings demonstrate the applicability of EP-enhanced DNA delivery to skin for gene therapy, DNA immunization and other areas.