Lisa Pan

Differential patterns of activity and functional connectivity in emotion processing neural circuitry to angry and happy faces in adolescents with and without suicide attempt

BACKGROUND Neural substrates of emotion dysregulation in adolescent suicide attempters remain unexamined. METHOD We used functional magnetic resonance imaging to measure neural activity to neutral, mild or intense (i.e., 0%, 50% or 100% intensity) emotion face morphs in two separate emotion-processing runs (angry and happy) in three adolescent groups: (1) history of suicide attempt and depression (ATT, n=14) ; (2) history of depression alone (NAT, n=15) ; and (3) healthy controls (HC, n=15). Post-hoc analyses were conducted on interactions from 3 group x 3 condition (intensities) whole-brain analyses (p<0.05, corrected) for each emotion run. RESULTS To 50% intensity angry faces, ATT showed significantly greater activity than NAT in anterior cingulate gyral–dorsolateral prefrontal cortical attentional control circuitry, primary sensory and temporal cortices; and significantly greater activity than HC in the primary sensory cortex, while NAT had significantly lower activity than HC in the anterior cingulate gyrus and ventromedial prefrontal cortex. To neutral faces during the angry emotion processing run, ATT had significantly lower activity than NAT in the fusiform gyrus. ATT also showed significantly lower activity than HC to 100% intensity happy faces in the primary sensory cortex, and to neutral faces in the happy run in the anterior cingulate and left medial frontal gyri (all p<0.006,corrected). Psychophysiological interaction analyses revealed significantly reduced anterior cingulate gyral–insula functional connectivity to 50% intensity angry faces in ATT v. NAT or HC. CONCLUSIONS Elevated activity in attention control circuitry, and reduced anterior cingulate gyral–insula functional connectivity, to 50% intensity angry faces in ATT than other groups suggest that ATT may show inefficient recruitment of attentional control neural circuitry when regulating attention to mild intensity angry faces, which may represent a potential biological marker for suicide risk.

Dissociable Patterns of Neural Activity During Response Inhibition in Depressed Adolescents With and Without Suicidal Behavior

OBJECTIVES Impaired attentional control and behavioral control are implicated in adult suicidal behavior. Little is known about the functional integrity of neural circuitry supporting these processes in suicidal behavior in adolescence. METHOD Functional magnetic resonance imaging was used in 15 adolescent suicide attempters with a history of major depressive disorder (ATTs), 15 adolescents with a history of depressive disorder but no suicide attempt (NATs), and 14 healthy controls (HCs) during the performance of a well-validated go-no-go response inhibition and motor control task that measures attentional and behavioral control and has been shown to activate prefrontal, anterior cingulate, and parietal cortical circuitries. Questionnaires assessed symptoms and standardized interviews characterized suicide attempts. RESULTS A 3 group by 2 condition (go-no-go response inhibition versus go motor control blocks) block-design whole-brain analysis (p < .05, corrected) showed that NATs showed greater activity than ATTs in the right anterior cingulate gyrus (p = .008), and that NATs, but not ATTs, showed significantly greater activity than HCs in the left insula (p = .004) to go-no-go response inhibition blocks. CONCLUSIONS Although ATTs did not show differential patterns of neural activity from HCs during the go-no-go response inhibition blocks, ATTs and NATs showed differential activation of the right anterior cingulate gyrus during response inhibition. These findings indicate that suicide attempts during adolescence are not associated with abnormal activity in response inhibition neural circuitry. The differential patterns of activity in response inhibition neural circuitry in ATTs and NATs, however, suggest different neural mechanisms for suicide attempt versus major depressive disorder in general in adolescence that should be a focus of further study.

Preserved hippocampal function during learning in the context of risk in adolescent suicide attempt

Impairment in decision-making is frequently observed in suicide attempters. Little is known, however, about neural circuitry underlying decision-making in adolescent attempters. Functional magnetic resonance imaging (fMRI) was used to assess decision-making and learning-related neural activity during Iowa Gambling Task (IGT) performance in adolescents with depression and suicide attempt (ATT, n=15), non-attempters with depression (NAT, n=14), and healthy controls (HC, n=13). ATT performed best on the IGT. A three group by two condition (high-risk versus low-risk) by three IGT block (each of 20 cards) whole-brain analysis (p<0.05, corrected) interaction was found in the left hippocampal, frontal and temporal cortical, striatal and thalamic regions. Post-hoc analyses revealed that during low-risk decisions in blocks 2 and 3, NAT, but not ATT, showed greater left hippocampal activation versus HC (p=0.0004, p=0.003); in block 2, during low-risk decisions NAT showed greater left middle temporal gyral activation versus HC (p=0.003); in block 3, during high-risk decisions ATT showed less activation in the right thalamus versus NAT (p=0.001) and during low risk decisions ATT showed greater activation than HC in the left caudate (p=0.002). NAT, but not ATT are differentiated from HC during performance of the IGT. Functional abnormalities in neural circuitry implicated in learning in the context of risk may underlie risk for MDD, but not risk for suicide attempt, in adolescence.

Functional neuroimaging studies of bipolar disorder: examining the wide clinical spectrum in the search for disease endophenotypes.

Bipolar disorder (BP) is among the top ten most disabling illnesses worldwide. This review includes findings from recent studies employing functional neuroimaging to examine functional abnormalities in neural systems underlying core domains of the psychopathology in BP: emotion processing, emotion regulation and executive control, and common comorbid features of BP, that are relevant to the wide spectrum of BP rather than focused on the more traditional BPI subtype, and that may facilitate future identification of diagnostically-relevant biomarkers of the disorder. In addition, an emerging number of studies are reviewed that demonstrate the use of neuroimaging to elucidate biomarkers whose identification may help to (1) identify at-risk individuals who will subsequently develop the illness to facilitate early intervention, (2) identify targets for treatment and markers of treatment response. The use of newer neuroimaging techniques and potential confounds of psychotropic medication upon neuroimaging findings in BP are also examined. These approaches will help to improve diagnosis and the mental well-being of all individuals with BP.

Neural Correlates of Treatment in Adolescents with Bipolar Depression During Response Inhibition

OBJECTIVE Abnormal prefrontal and subcortical activity during cognitive control tasks is identified in non-depressed adolescents with bipolar disorder (BD); however, little is known about the neural correlates of bipolar adolescents in a depressed state (BDd). We aimed to investigate baseline versus after-treatment patterns of neural activity underlying motor response and response inhibition in adolescents with BDd. METHODS In this functional magnetic resonance imaging (fMRI) study, 10 adolescents with BDd relative to 10 age- and sex-matched healthy controls (HC) completed a well-validated go/no go block-design cognitive control task at baseline and after 6 weeks of naturalistic treatment. We used whole-brain analysis and controlled our results for multiple comparisons. RESULTS There was significant improvement in depression scores (mean change: 57%±28). There was no behavioral difference in BDd baseline versus HC and after treatment. BDd adolescents relative to HC had higher baseline cortical, but not subcortical, neural activity (e.g., bilateral ventrolateral prefrontal during both the go [motor control] and the no go [response inhibition] conditions, and left superior temporal during the no go condition). However, after-treatment activity relative to baseline neural activity during response inhibition was significantly increased in subcortical (e.g., right hippocampus and left thalamus), but not cortical, regions. In addition, at baseline, lower left thalamus activity was correlated with higher depression scores. CONCLUSIONS Adolescents with BDd had baseline prefrontal and temporal hyperactivity underlying motor control and response inhibition that did not change after treatment in contrast to relatively decreased baseline subcortical activity underlying response inhibition associated with the depressive state that was increased after the treatment.

Magnetic resonance imaging markers of suicide attempt and suicide risk in adolescents.

More than 36,000 people in the United States die from suicide annually, and suicide is the third leading cause of death in adolescence. Adolescence is a time of high risk for suicidal behavior, as well as a time that intervention and treatment may have the greatest impact because of structural brain changes and significant psychosocial development during this period. Functional and structural neuroimaging studies in adults who have attempted suicide suggest distinct gray matter volume abnormalities in cortical regions, as well as prefrontal cortical and dorsal anterior cingulate gyrus neural circuitry differences compared with affective and healthy adult controls. Recent functional neuroimaging studies in adolescents with a history of suicide attempt suggest differences in the attention and salience networks compared with adolescents with depression and no history of suicide attempt and healthy controls when viewing angry faces. In contrast, no abnormalities are seen in these areas in the absence of emotional stimuli. These networks may represent promising targets for future neuroimaging studies to identify markers of risk for future suicide attempt in adolescents.

Right superior temporal gyrus volume in adolescents with a history of suicide attempt

The extent to which observed differences in emotion processing and regulation neural circuitry in adolescents with a history of suicide attempt are paralleled by structural differences is unknown. We measured brain cortical thickness and grey- and white-matter volumes in 100 adolescents: 28 with a history of suicide attempt and major depressive disorder (MDD); 31 with a history of MDD but no suicide attempt; and a healthy control group (n = 41). The first group compared with controls showed reduction in grey-matter volume in the right superior temporal gyrus (BA38), a region important for social emotion processing.

Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior

OBJECTIVE Treatment-refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. At least 15% of cases of major depressive disorder remain refractory to treatment. The authors previously identified a young adult with treatment-refractory depression and multiple suicide attempts with an associated severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. Treatment with sapropterin, a tetrahydrobiopterin analogue, led to dramatic and long-lasting remission of depression. This sentinel case led the authors to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is underrecognized. METHOD The authors conducted a case-control, targeted, metabolomic evaluation of 33 adolescent and young adult patients with well-characterized histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments), and 16 healthy comparison subjects. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry and high-performance liquid chromatography electrospray ionization tandem mass spectrometry. RESULTS CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (N=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin. None of the healthy comparison subjects had a metabolite abnormality. CONCLUSIONS Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.

Altered neural function to happy faces in adolescents with and at risk for depression

BACKGROUND There is accumulating evidence of alterations in neural circuitry underlying the processing of social-affective information in adolescent Major Depressive Disorder (MDD). However the extent to which such alterations are present in youth at risk for mood disorders remains unclear. METHOD Whole-brain blood oxygenation level-dependent task responses and functional connectivity using generalized psychophysiological interaction (gPPI) analyses to mild and intense happy face stimuli was examined in 29 adolescents with MDD (MDD; M age, 16.0, S.D. 1.2 years), 38 healthy adolescents at risk of a mood disorder, by virtue of having a parent diagnosed with either Bipolar Disorder (BD) or MDD (Mood-risk; M age 13.4, S.D. 2.5 years) and 43 healthy control adolescents, having parents with no psychiatric disorder (HC; M age 14.6, S.D. 2.2 years). RESULTS Relative to HC adolescents, Mood-risk adolescents showed elevated right dorsolateral prefrontal cortex (DLPFC) activation to 100% intensity happy (vs. neutral) faces and concomitant lowered ventral putamen activity to 50% intensity happy (vs. neutral) faces. gPPI analyses revealed that MDD adolescents showed significantly lower right DLPFC functional connectivity with the ventrolateral PFC (VLPFC) compared to HC to all happy faces. LIMITATIONS The current study is limited by the smaller number of healthy offspring at risk for MDD compared to BD. CONCLUSIONS Because Mood-risk adolescents were healthy at the time of the scan, elevated DLPFC and lowered ventral striatal activity in Mood-risk adolescents may be associated with risk or resiliency. In contrast, altered DLPFC-VLPFC functional connectivity in MDD adolescents may be associated with depressed mood state. Such alterations may affect social-affective development and progression to a mood disorder in Mood-risk adolescents. Future longitudinal follow-up studies are needed to directly answer this research question.

Toward identification of neural markers of suicide risk in adolescents

Suicide remains a leading cause of adolescent morbidity and mortality. Despite identification of risk factors and protective factors for suicidal behavior, we have limited understanding of the mechanisms underlying risk for suicide attempt. Adolescence is a time of high risk for suicidal behavior, as well as a time that intervention and treatment may have the greatest impact because of structural brain changes and significant psychosocial development during this period. Functional magnetic resonance imaging (fMRI) studies have promise to yield markers of risk for suicidal behavior in adolescents because they can help identify neurobiological underpinnings of pathophysiologic mechanisms that are not observable at the behavioral level, and can also provide targets for future neurobiological interventions. Markers of risk for suicidal behavior are beginning to be elucidated, but as yet have not been applied to the clinical management of adolescents at risk for suicide. Neuroimaging studies indicate neural circuitry abnormalities in adult suicide attempters. One study in adult suicide attempters reported lower glucose uptake in the prefrontal cortex and dorsal anterior cingulate gyrus in high vs low lethality suicide attempters (Oquendo et al, 2003). With regard to emotion processing, vulnerability to suicidal behavior has been associated with differences in response to negative emotion. Specifically, adult male suicide attempters showed greater activity in the right lateral orbitofrontal cortex and decreased activity in the right superior frontal gyrus to intense angry vs neutral faces relative to healthy and depressed non-attempter controls. In addition, cognitive inflexibility (inability to change strategy) is well documented in studies of adult patients with a history of suicide attempt (Jollant et al, 2005). However, few studies have explored the neural circuitry underlying adolescent suicidal behavior. This is an important oversight because suicide is one of the leading causes of death in adolescence, and the developing brain may provide a window into risk for suicidal behavior and allow for earlier intervention to prevent suicide. Our functional neuroimaging studies indicate differences in emotion processing in adolescents with history of depression and suicide attempt relative to healthy control adolescents. Here, we have shown differences in the attention and salience networks (Pan et al, 2013). Our findings differ from those in adult males with depression, in whom the functional connectivity of the striatal-anterior cortical midline structures circuit is implicated in suicidal ideation (Marchand et al, 2012). Specifically, we have shown increased attentional control network activity and decreased functional connectivity between the dorsal anterior cingulate gyrus, implicated in attentional control of emotion, and the insula, a neural region associated with interoceptive processing of emotion, when viewing angry faces in adolescents with a history of depression and suicide attempt compared with healthy controls and depressed adolescent non-attempters (Figure 1). In contrast, adolescents with a history of depression and suicide attempt showed no abnormalities in levels of performance accuracy or dorsal anterior cingulate activity and attentional control network activity on tasks of cognitive control and learning in the context of risk (Pan et al, 2011, 2013). Together, these findings suggest that abnormal functioning of the salience and attention networks in the setting of emotion processing, with normal function in these networks in the absence of emotional stimuli, may represent markers of past suicide attempt. These networks are thus promising foci for future neuroimaging studies aiming to identify markers of risk for future suicide attempt in adolescent populations.