Brain Basis for Emotion Recognition Deficits in Depression

There is a emerging understanding of the role of social perception problems in depression and anxiety disorders.  Depression appears to effect the cognitive ability to judge the facial expression of others.  This impairment poses a challenge for interpersonal function and social relationships.  Research is now pinning down the neural basis for this deficit and to determine it’s persistence and the effect of depression remission on this social cognition function.

van Wingen and colleagues from the Netherlands recently published an fMRI study on this topic in Psychological Medicine.  The study had the following elements in research design:

• Subjects: Twenty case subjects with first episode of major depression (medication naive), Twenty one case subjects recovered from a first episode of depression and 30 healthy individuals without a history of depression
• f MRI Task: Visual recognition of anger or fearful face by semantic labelling or visual matching compared to a control task of matching facial orientation without attention to emotion
• Additional Neuropsychological Testing: Depression symptom level, anxiety (state and trait) symptom level, IQ, memory, visual learning, attention, psychomotor speed and executive function.

The depression case subjects were not different from recovered depressed subjects and controls on most of the tests of neuropsychological function.  As expected, they did have higher depression symptom severity scores (Hamilton Depression Scale average for the depressed group was 21.8) and higher anxiety symptom severity scores.

The depressed group performed as well as the remitted group on the control task and the visual emotion matching task.  However, they performed worse than both groups on the semantic matching task, i.e. selecting the correct word label for the emotion displayed visually.  

The brain regions that correlated (increased activation) with impaired semantic emotion labeling included three distinct regions:

• right amygdala
• left inferior frontal gyrus
• anterior cingulate cortex

The authors propose that one explanation for this finding in three distinct brain regions.

“The left inferior frontal gyrus is thought to integrate language with other information (Hagoort, 2005;Willems et al. 2007). Therefore, we suggest that the inferior frontal gyrus may integrate the semantic knowledge about the concepts of anger and fear with the emotional information conveyed by the faces by interacting with the amygdala. The concurrent activation of these systems may subsequently trigger automatic negative thoughts and stimulate task unrelated processes such as rumination (Siegle et al. 2002; Ray et al. 2005), and thereby hinder task appropriate behaviour.”

This explanation fits with the cognitive behavioral theory of depression.  The core concept being that depression is characterized by increased automatic negative thoughts about the self, the future and the environment.  The thoughts are generated by a maladaptive negative cognitive schema.  Activation of these automatic thoughts (i.e. by being shown negative facial emotions) produces distraction from tasks (i.e. correctly labelling these facial emotions). This process appears limited to when depression is present as the recovered depression group showed no deficit.

The authors also conclude the findings could be due to a compensatory mechanism for inadequate behavior or an altered coping mechanism for dealing with demanding situations. 

This study provides additional support that fMRI research may lead to advances in the treatment of depression by both psychotherapy and psychopharmacologic interventions.

Screen shot of 3D Brain showing the limbic system structures amygdala and cingulate cortex (along with the inferior frontal cortex) thought to be involved in impaired facial recogniton in depression.

van Wingen, G., van Eijndhoven, P., Tendolkar, I., Buitelaar, J., Verkes, R., & Fernández, G. (2010). Neural basis of emotion recognition deficits in first-episode major depression Psychological Medicine, 41 (07), 1397-1405 DOI: 10.1017/S0033291710002084

Anxiety as a Gut Feeling: Understanding Interoception

Marcus Paulus presented the April 2011 Warren Neuroscience Frontiers in Neuroscience Lecture.  The presentation was titled: Interoception and Anxiety.

Interoception is the summation of a variety of bodily perceptions that make up the integrated sense of our own physiological state.  Perceptions included in interoception include: pain, temperature, tickle, sensual touch, stomach discomfort to due acidity, air hunger and muscle tension.  Here are my notes from Dr. Paulus' presentation and his research manuscript on this topic area.

• Anxiety proneness is a trait that can be measured and is associated with high risk of later development of an anxiety disorder
• Anxiety proneness linked to increased activation of the dorsal amygdala and the anterior insula in brain fMRI tasks such as the Emotion Face Assessment task of Hariri
• Patients with anxiety also show insular hyperactivation in anticipation of negative cues
• Benzodiazepines like Valium reduce activation of the insula as well as the amygdala in response to angry faces

• There is growing awareness the brain insular cortex plays a key role in interoception--receiving signals from the body and integrating these signals with emotional response and regulation (see a previous post summarizing the function of the insula and possible roles in clinical neuroscience disorders)
• The insula also connects to a central pathway important in anxiety involving the anterior cingulate cortex and the dorsolateral prefrontal cortex--these areas provide input to the insula for planning and acting in the face of

• Key properties of the interoception include the signals from internal organs including the lungs, heart, gastrointestinal tract and genitourinary systems
• Many of these signals provide awareness of body and help promote homeostasis
• These signals also are involved in our sense of self and the passing of time

• A new area of understanding is the important role of personal beliefs in emotional processing--personal beliefs may modulate interoception and the perception of emotional cues
• A belief that a situation or cue is more dangerous than it really is, i.e. I will embarrass myself at the party, can modulate how emotion is processed, and can amplify a anxious response to the situation

Future research in the area of interoception and anxiety will target:

• Genetic influences on interoception
• How cognitive interventions may influence dysfunctional beliefs related to anxiety
• How interoception may help with more biological classification of types of anxiety
• Can people be trained to up or down regulate the insular cortex to reduce anxiety?
• How treatments for anxiety effect the elements of interoception

Brain Tutor iPad Screenshot of Insular Cortex in Green Courtesy of Author

Paulus MP, & Stein MB (2010). Interoception in anxiety and depression. Brain structure & function, 214 (5-6), 451-63 PMID: 20490545

Decoding the Faces of Depression: Anhedonia and Dopamine

Diego Pizzagalli presented the March 2011 Warren Frontiers in Neuroscience Series lecture in Tulsa, Oklahoma on March 1, 2011.  Dr. Pizzagalli works at the Harvard Medical School affiliated Center for Depression, Anxiety and Stress Research & Neuroimaging Center at McLean Hospital in Boston.  He has been involved in research related to brain abnormalities in major depression as well as predictors of treatment response.  I will highlight some of the key points from his lecture and incorporate three recent research manuscripts related to this topic:

• There are over 100 symptom combinations to diagnosis major depression (5 of 9 symptoms required)
• Distinct depressive phenotypes (clinical presentations) are difficult to define--but the phenotype defined by anhedonia (pervasive lack of ability to experience pleasure) has significant research support
• Depression with anhedonia also has a biological component--the brain reward pathways involving dopamine and the striatum.
• Anhedonia has been linked to impaired dopamine function in these brain reward pathways
• Anhedonia appears more heritable than depression and may be related to abnormalities in genes controlling dopamine neurotransmission
• The dopamine reward pathway (substantia nigra-striatum-cingulate/prefrontal cortex) is vulnerable to stress (acute stress increases dopamine, chronic stress reduces it in the rat model)
• He and colleagues developed a heuristic model of the functional neuroanatomy of anhedonia: both environmental and biological factors influence risk of depression: depression includes a decrease in the brains reward response, exaggerated stress responsivity and eventually a blunted mesolimbic dopamine system (and anhedonia)
• Laboratory models and psychometric measures of anhedonia have been developed--studies suggest the ventral striatum (nucleus accumbens) is involved in hedonic coding while the dorsal striatum (caudate) is involved in positive re-inforcement
• Decreased activation of cingulate and caudate with monetary incentive delay task is seen in untreated depression
• Untreated depression (and anhedonia) also linked to decreased size of the caudate
• Early life stress (abuse) may increase depression risk through dysregulation of mesolimbic pathways including left putamen and left pallidum
• Stress even in healthy individuals impairs brains reward processing pathway
• Some genes related to anhedonia may work through stress pathways, i.e. mineralcorticoids, corticotrophin hormone (CRH)
• Future research will focus on further parsing of the heterogeneity associated with depression, developing animal models of reward tasks, using PET to better understand the role of dopamine in depression, using dopaminergic drugs (i.e. pramipexole) in stimulation models of depression and further study of the neurobiology of stress-induced anhedonia

I agree that evaluating the role of dopaminergic drugs in depression accompanied by anhedonia is worthy of basic and clinical research study.  Among typical antidepressants, only bupropion appears to have dopaminergic effects.  Other compounds such as psychostimulants also increase dopamine but carry the risk for abuse.  Several of the dopaminergic drugs used for Parkinson disease are beginning to see more use off-label for the treatment of depression.  I will look at this issue in a future Brain Post. 

Photo of Blake Griffin shooting free throw against Oklahoma City Thunder in 2011 NBA game courtesy of Tim Yates.

Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, Dougherty DD, Iosifescu DV, Rauch SL, & Fava M (2009). Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. The American journal of psychiatry, 166 (6), 702-10 PMID: 19411368

Wacker J, Dillon DG, & Pizzagalli DA (2009). The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques. NeuroImage, 46 (1), 327-37 PMID: 19457367

Pizzagalli DA (2011). Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36 (1), 183-206 PMID: 20861828

Lupus May Involve Brain Long Before CNS Symptoms

The brain manifestions of systemic lupus erthematosis can be quite variable.  Many patients do not experience any central nervous system symptoms.  Others can be quite disabled by their CNS symptoms including severe depression, psychosis and delirium.  This variability in the brain is not surprising given that lupus involves a variety of other organ systems (i.e. cardiac) with a range of effects specific to individuals with the disorder. 

A group of Chinese radiologists and rheumatologists have published some interesting work on lupus and the brain.  They wanted to answer the question: “Do patients with lupus without CNS symptoms truly have no evidence of CNS disease?”  To answer that question, they looked at a sensitive research marker of brain function known as the default network using functional magnetic resonance imaging.  Here are the key elements of their study:

• Cases=33 right-handed female subjects with no neuropsychiatric symptoms (two were later excluded due to obvious brain abnormalities on typical MRI images (T1 or T2)
• Controls=23 right-handed female subjects recruited from the community matched by age
• Resting brain images were compared for regional homogeneity—this default network strategy examines synchronicity between brain regions felt to indicate network connections

The Chinese research team found that multiple areas of the brain decreased homogeneity in the lupus group.  Areas noted to be impaired included the cerebellum, the left inferior frontal gyrus, the left precuneus area, the right limbic lobe and the cingulate gyrus.   Using a marker of brain lupus activity, they were able to identify involvement of disease activity in the cerebellum and the left anterior cingulate gyrus.  This suggests that these specific regions of interest (ROI) identified in the default -network study may indeed be involved in the CNS pathology of lupus.

The authors conclude that lupus may produce significant brain changes in the absence of overt CNS symptoms.  These changes appear to not be spotty focal effects but appear to involve multiple brain networks.  They note lupus may have specific detrimental effects involving the cerebellum that could play a role in the neuropsychiatric manifestions of the disease.

Photo of Pelicans Feeding on Arkansas River Courtesy of Yates Photography

Lin Y, Zou QH, Wang J, Wang Y, Zhou DQ, Zhang RH, Zhang YW, Lii HT, & Fang YF (2010). Localization of cerebral functional deficits in patients with non-neuropsychiatric systemic lupus erythematosus. Human brain mapping PMID: 21170956

Risk Factors in Children with a Bipolar Parent

Dr. Audie Henin presented the October 2010 lecture for the Warren Frontiers of Neuroscience series on October 5, 2010.  Her presentation “Familial, Neurobiological and Cognitive Risk Factors for Bipolar Disorder in Youth” will be summarized in my notes below.  Dr. Henin is an associate professor at Harvard University and is affiliated with Massachussetts General Hospital.

Dr. Henin and her research team have been involved in a series of studies in high-risk children focusing on a variety of emotional disorders including ADHD, depression and bipolar disorder.  High-risk studies in children typically include children whose parents suffer from a mental disorder.  High-risk bipolar studies in children typically include children with at least one parent with bipolar disorder.  Risk of bipolar disorder has been estimated at 25% for those with one parent with bipolar disorder and between 50 and 75% for those with both parents having the disorder.

Dr. Henin’s follow-up study of bipolar high-risk children confirms the risk for early onset of a mood disorder in this group—50% have met criteria for major depression by age 18 with 30% exhibiting an episode of mania and therefore meeting criteria for a diagnosis of bipolar disorder.

Children of a parent with bipolar disorder have increased rates of emotional disorder above and beyond the mood disorder category. This group of children also was found to have increased risk for an anxiety disorder, substance use disorders, ADHD and other disruptive behavior disorders such as oppositional defiant disorder and conduct disorder.  Since many of these disorders occur before the typical age of onset of bipolar disorder, they may signal a higher risk for later onset of bipolar disorder.  These children also demonstrated high rates of a temperament type characterized by disinhibition—a tendency to take risks in novel environmental settings.

Identifying risk factors for bipolar disorder in this high risk sample requires controlling for effects of diagnostic comorbidity in parents and controlling for the potential effects of medication use.  Parental anxiety disorders and substance use disorders increase risk for substance in the high-risk children.  Children developing bipolar disorder show neuropsychological impairments found in adult bipolar populations including deficits in executive function (planning, organization, multi-stage goal directed behavior), working memory, attention, mathematical skills and verbal memory.   However, many of these cognitive problems may be attributable to ADHD or worsened by the co-occurence of ADHD.  


Examining the role of medication, the Harvard group found a link between mood stabilizer drug use (i.e. lithium and valproate) and slowed cognitive processing.  Some of the neuropsychological deficits found in children with bipolar disorder are also present in their siblings who do not yet meet criteria for a bipolar disorder diagnosis. 

Neuroimaging studies in this high-risk child and adolescent sample suggests reduced glutamine and myoinositol in the anterior cingulate cortex.  This suggests reduction in brain glial cells in this brain region.  Unaffected sibs and those with partial symptoms show higher anterior cingulate glutamine, possibly a protective factor for the full expression of the disorder.

Dr. Henin concluded her presentation with a brief summary of a psychotherapy model to treat adolescents and young adults with bipolar disorder.  This program combines cognitive behavior therapy with elements of motivational interviewing to reduce the frequency of problem behaviors.  The study is ongoing but preliminary findings support the intervention as more effective than wait list in overall improvement and reducing risk behavior frequency. 

Given the high number of concurrent other emotional disorders in bipolar high-risk children, diagnosis is a complex process.  Often longitudinal follow-up, symptom monitoring, assessing response to drug therapy and using a family members perspectives are required for accurate diagnosis.  Additional research is necessary to aid clinicians in the diagnostic process and to inform improved treatment and prevention strategies. 

Photo of U.S. Ryder Cup golfer Hunter Mahan (Camillo Villegas in backgroung) at 2010 PGA Championship.

Henin A, Biederman J, Mick E, Sachs GS, Hirshfeld-Becker DR, Siegel RS, McMurrich S, Grandin L, & Nierenberg AA (2005). Psychopathology in the offspring of parents with bipolar disorder: a controlled study. Biological psychiatry, 58 (7), 554-61 PMID: 16112654


Henin A, Mick E, Biederman J, Fried R, Wozniak J, Faraone SV, Harrington K, Davis S, & Doyle AE (2007). Can bipolar disorder-specific neuropsychological impairments in children be identified? Journal of consulting and clinical psychology, 75 (2), 210-20 PMID: 17469879