Abnormal functional connectivity of the medial cortex in euthymic bipolar II disorder.

This project utilized functional MRI (fMRI) and a motor activation paradigm to investigate neural circuitry in euthymic bipolar II disorder. We hypothesized that circuitry involving the cortical midline structures (CMS) would demonstrate abnormal functional connectivity. Nineteen subjects with recurrent bipolar disorder and 18 controls were studied using fMRI and a motor activation paradigm. We used functional connectivity analyses to identify circuits with aberrant connectivity. We found increased functional connectivity among bipolar subjects compared to healthy controls in two CMS circuits. One circuit included the medial aspect of the left superior frontal gyrus and the dorsolateral region of the left superior frontal gyrus. The other included the medial aspect of the right superior frontal gyrus, the dorsolateral region of the left superior frontal gyrus and the right medial frontal gyrus and surrounding region. Our results indicate that CMS circuit dysfunction persists in the euthymic state and thus may represent trait pathology. Future studies should address whether these circuits contribute to relapse of illness. Our results also suggest the possibility that aberrations of superior frontal circuitry may impact default mode network and cognitive processes.

Striatal circuit function is associated with prior self-harm in remitted major depression.

The neural processes underlying suicide risk are incompletely characterized. This project utilized functional MRI (fMRI) to determine whether a history of self-harm was associated with striatal circuit function in recurrent major depression in remission. Twenty unmedicated subjects with recurrent major depression and 21 controls were studied using fMRI and a motor activation paradigm. We used functional connectivity analyses to identify circuits with aberrant connectivity. We also used correlational analyses to determine whether functional connectivity was associated with a history of self-harm. There was a significant association between history of self-harm and functional connectivity of a striatal-motor circuit. Additionally, striatal and cortical midline circuits exhibited decreased functional connectivity in remitted unipolar depression as compared to controls. Our previous study of individuals experiencing an episode of depression indicated an association between striatal circuitry and a history of self-harm. That study, along with the results reported herein suggests striatal circuit function may play a key role in the neurobiology of suicide and self-harm risk in recurrent major depression. Our results also indicate that both striatal and CMS circuit dysfunction persists in the euthymic state of recurrent major depression and thus may represent trait pathology.

Differences in functional connectivity in major depression versus bipolar II depression.

BACKGROUND: Objective methods of differentiating unipolar versus bipolar depression would enhance our ability to treat these disorders by providing more accurate diagnoses. One first step towards developing diagnostic methodology is determining whether brain function as assessed by functional MRI (fMRI) and functional connectivity analyses might differentiate the two disorders. METHODS: Fourteen subjects with bipolar II depression and 26 subjects with recurrent unipolar depression were studied using fMRI and functional connectivity analyses. RESULTS: The first key finding of this study was that functional connectivity of the right posterior cingulate cortex differentiates bipolar II and unipolar depression. Additionally, results suggest that functional connectivity of this region is associated with suicidal ideation and depression severity in unipolar but not bipolar II depression. LIMITATIONS: The primary limitation is the relatively small sample size, particularly for the correlational analyses. CONCLUSIONS: The functional connectivity of right posterior cingulate cortex may differential unipolar from bipolar II depression. Further, connectivity of this region may be associated with depression severity and suicide risk in unipolar but not bipolar depression.

Aberrant functional connectivity of cortico-basal ganglia circuits in major depression.

There is considerable evidence of functional abnormalities of the cortico-basal ganglia circuitry in affective disorders. However, it has been unknown whether this represented primary pathology within these circuits or altered activation as a result of aberrant input from other brain regions. The aim of this study was to test the hypothesis that cortico-basal ganglia circuit dysfunction represents primary pathology in unipolar depression. Eighteen male subjects with recurrent unipolar depression and eighteen controls without psychiatric illness were studied using functional MRI and functional connectivity analyses. All unipolar subjects were unmedicated and without current psychiatric comorbidity. Compared to controls, unipolar subjects exhibited altered connectivity between bilateral subcortical components of the circuitry (putamen-thalamus) and left hemisphere input and output components. Results provided evidence that functional abnormalities of these circuits represent primary pathology. Further, we found that age of onset but not duration of illness impacts circuit function. These findings suggest that the cortico-basal ganglia circuitry is likely one of several loci of primary pathology in major depression. Additionally, early age of onset is associated with greater circuit abnormality and as such may impact clinical characteristics and/or treatment response through a mechanism of decreasing functional connectivity of some circuit segments. Finally, altered cortico-basal ganglia circuit connectivity with cortical regions (anterior cingulate, inferior frontal gyrus and sensorimotor) may contribute to the emotional dysregulation, impaired emotional recognition and psychomotor symptoms associated with unipolar illness.

Striatal and cortical midline circuits in major depression: implications for suicide and symptom expression.

BACKGROUND: In major depression, the neural mechanisms underlying suicide related thoughts and behaviors as well as the expression of other depressive symptoms are incompletely characterized. Evidence indicates that both the striatum and cortical midline structures (CMS) may be involved with both suicide and emotional dysregulation in unipolar illness. The aim of this study was to identify striatal-CMS circuits associated with current depression severity and suicidal ideation (SI) as well as a history of self-harm. METHODS: Twenty-two male subjects with recurrent unipolar depression were studied using functional MRI. All subjects were unmedicated and without current psychiatric comorbidity. Correlational analyses were used to determine whether striatal-CMS functional connectivity was associated with any of the three clinical variables. RESULTS: A network involving the bilateral striatum and anterior CMS was found to be associated with depressive symptom severity. Current SI was associated with a similar but less extensive circuit in the left hemisphere. A distinct striatal motor/sensory network was associated with self-harm behaviors, but not current SI or depression severity. CONCLUSIONS: The striatal-anterior CMS circuit likely plays a significant role in the expression of depressive symptoms and SI. In contrast, a striatum-motor/sensory cortex network may be a trait marker of suicide-related behaviors. If replicated, this result might eventually lead to the development of a biomarker that would be useful for studies of pharmacologic and/or psychotherapeutic suicide prevention interventions.

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.

Personality disorder in ADHD Part 1: Assessment of personality disorder in adult ADHD using data from a clinical trial of OROS methylphenidate.

BACKGROUND: Comorbidity of personality disorder (PD) and attention-deficit/hyperactivity disorder (ADHD) has been suggested in several reports. However, assessment of PD is problematic, and studies have over-relied on baseline evaluations. METHODS: Forty-seven patients entered a double-blind trial of osmotic release oral system (OROS) methylphenidate (MPH). Patients were assessed at baseline with the Wisconsin Personality Inventory IV (WISPI-IV) and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Following the study, all information-including tests, family reports, and extended clinical observations-produced a final PD diagnosis. Three post hoc categories were created: PD-negative (no PD), PD-positive (1 PD), and PD-plus (2 or more PDs). RESULTS: Twenty-one (45%) patients had a PD on the final assessment vs 62% using SCID-II and 33% using WISPI-IV; final PD diagnosis revealed 9% cluster A, 17% cluster B, and 28% cluster C. Twenty-one percent of patients experienced multiple disorders. Using a weighted kappa, the number of PDs on the final assessment correlated with the WISPI-IV (kappa=.53; P > .001) and the SCID-II (kappa =.70; P < .001). However the SCID-II overidentified and the WISPI-IV underidentified PD. CONCLUSION: Almost all PDs were represented in this sample, and past emphasis on cluster B appears unwarranted. Although the SCID-II and WISPI-IV had limited success in identifying specific PDs, they were more successful in identifying the number of PDs present in each patient. The small sample makes these findings preliminary.

Personality disorders in ADHD Part 2: The effect of symptoms of personality disorder on response to treatment with OROS methylphenidate in adults with ADHD.

BACKGROUND: This study explored the relationship between personality disorder (PD) and treatment response in a randomized, double-blind, clinical trial of osmotic release oral system (OROS) methylphenidate (MPH). METHODS: Forty-seven patients entered a crossover trial using the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) to assess outcome. A final personality diagnosis was made using staff consensus and information from the Wisconsin Personality Inventory IV (WISPI-IV) and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Three post hoc categories were created: PD-negative (no PD; n = 26), PD-positive (patients with 1 PD; n = 11), and PD-plus (patients with 2 or more PDs; n = 10). Improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms was assessed using a mixed-model analysis with treatment and personality categories as fixed variables. Average z scores on the WISPI-IV and items endorsed on SCID-II provided dimensional measures of PD severity. RESULTS: Different treatment effects were observed for the PD subgroups (P < .001). PD-negative patients improved 40% on OROS MPH vs 7% on placebo, and PD-positive patients improved 66% on OROS MPH vs 9% on placebo. In contrast, PD-plus patients improved 26% on OROS MPH vs 23% on placebo. CONCLUSION: Most patients experienced significantly reduced ADHD symptoms on OROS MPH; however, patients with 2 or more PDs did not. The 2 alternate measures of PD supported this observation in this small exploratory study.

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.