Deep brain stimulation of the internal capsule enhances human cognitive control and prefrontal cortex function.

Deep brain stimulation (DBS) is a circuit-oriented treatment for mental disorders. Unfortunately, even well-conducted psychiatric DBS clinical trials have yielded inconsistent symptom relief, in part because DBS' mechanism(s) of action are unclear. One clue to those mechanisms may lie in the efficacy of ventral internal capsule/ventral striatum (VCVS) DBS in both major depression (MDD) and obsessive-compulsive disorder (OCD). MDD and OCD both involve deficits in cognitive control. Cognitive control depends on prefrontal cortex (PFC) regions that project into the VCVS. Here, we show that VCVS DBS' effect is explained in part by enhancement of PFC-driven cognitive control. DBS improves human subjects' performance on a cognitive control task and increases theta (5-8Hz) oscillations in both medial and lateral PFC. The theta increase predicts subjects' clinical outcomes. Our results suggest a possible mechanistic approach to DBS therapy, based on tuning stimulation to optimize these neurophysiologic phenomena.

Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

Physical Exercise for Treatment of Mood Disorders: A Critical Review.

PURPOSE OF THE REVIEW: The purpose of this review is to critically assess the evidence for exercise as an adjunct intervention for major depressive disorder and bipolar disorder, chronic conditions characterized by frequent comorbid conditions as well as interepisodic symptoms with poor quality of life and impaired functioning. Individuals with these mood disorders are at higher risk of cardiovascular disease and premature death in part because of increased rates of obesity, inactivity, and diabetes mellitus compared to the general population. Exercise may not only mitigate the increased risk of cardiovascular disease, but could also potentially improve the long term outcomes of mood disorders. RECENT FINDINGS: We conducted a literature review on the impact of exercise on mood disorders and associated comorbid conditions as well as possible biological mechanisms. We found that exercise impacts both the physical health parameters of mood disorders as well as mental health outcomes. Exercise also positively impacts conditions frequently comorbid with mood disorders (i.e. anxiety, pain, and insomnia). There are multiple candidate biomarkers for exercise, with brain-derived neurotrophic factor and oxidative stress as two main promising components of exercise's anti-depressant effect. SUMMARY: Exercise appears to be a promising adjunct treatment for mood disorders. We conclude with recommendations for future research of exercise as an adjunct intervention for mood disorders.

Pilot randomized trial demonstrating reversal of obesity-related abnormalities in reward system responsivity to food cues with a behavioral intervention.

OBJECTIVES: Obesity is associated with hyperactivation of the reward system for high-calorie (HC) versus low-calorie (LC) food cues, which encourages unhealthy food selection and overeating. However, the extent to which this hyperactivation can be reversed is uncertain, and to date there has been no demonstration of changes by behavioral intervention. SUBJECTS AND METHODS: We used functional magnetic resonance imaging to measure changes in activation of the striatum for food images at baseline and 6 months in a pilot study of 13 overweight or obese adults randomized to a control group or a novel weight-loss intervention. RESULTS: Compared to controls, intervention participants achieved significant weight loss (-6.3±1.0 kg versus +2.1±1.1 kg, P<0.001) and had increased activation for LC food images with a composition consistent with that recommended in the behavioral intervention at 6 months versus baseline in the right ventral putamen (P=0.04), decreased activation for HC images of typically consumed foods in the left dorsal putamen (P=0.01). There was also a large significant shift in relative activation favoring LC versus HC foods in both regions (P<0.04). CONCLUSIONS: This study provides the first demonstration of a positive shift in activation of the reward system toward healthy versus unhealthy food cues in a behavioral intervention, suggesting new avenues to enhance behavioral treatments of obesity.

Age at onset, course of illness and response to psychotherapy in bipolar disorder: results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

BACKGROUND: The course of bipolar disorder progressively worsens in some patients. Although responses to pharmacotherapy appear to diminish with greater chronicity, less is known about whether patients' prior courses of illness are related to responses to psychotherapy. METHOD: Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy with collaborative care (a three-session psycho-educational intervention). We assessed whether the number of previous mood episodes, age of illness onset, and illness duration predicted or moderated the likelihood of recovery and time until recovery from a depressive episode in patients in the two treatments. RESULTS: Independently of treatment condition, participants with one to nine prior depressive episodes were more likely to recover and had faster time to recovery than those with 20 or more prior depressive episodes. Participants with fewer than 20 prior manic episodes had faster time to recovery than those with 20 or more episodes. Longer illness duration predicted a longer time to recovery. Participants were more likely to recover in intensive psychotherapy than collaborative care if they had 10-20 prior episodes of depression [number needed to treat (NNT) = 2.0], but equally likely to respond to psychotherapy and collaborative care if they had one to nine (NNT = 32.0) or >20 (NNT = 9.0) depressive episodes. CONCLUSIONS: Number of previous mood episodes and illness duration are associated with the likelihood and speed of recovery among bipolar patients receiving psychosocial treatments for depression.

Illness burden and medical comorbidity in the Systematic Treatment Enhancement Program for Bipolar Disorder.

OBJECTIVE: Coexisting chronic medical conditions are common in bipolar disorder. Here, we report the prevalence and correlates of medical comorbidity in patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). We were particularly interested in associations between variables reflecting illness chronicity and burden with comorbid medical conditions. METHOD: We used intake data from the open-label component of the STEP-BD. History of medical comorbidity was obtained from the affective disorders evaluation, and its presence was the outcome of interest. The sample size in analyses varied from 3399 to 3534. We used multiple Poisson regression to obtain prevalence ratios. RESULTS: The prevalence of any medical comorbidity in the sample was 58.8%. In addition to demographic variable, several clinical characteristics were associated with the frequency of medical comorbidity. Having more than 10 previous mood episodes, childhood onset, smoking, lifetime comorbidity with anxiety, and substance use disorders were independently associated with having a medical comorbidity in the final multivariate model. CONCLUSION: The results presented here reveal strong associations between variables related to illness chronicity and medical burden in bipolar disorder. This lends further support to recent multidimensional models incorporating medical morbidity as a core feature of bipolar disorder.

Characteristics of non-verbal memory impairment in bipolar disorder: the role of encoding strategies.

BACKGROUND: There is evidence that individuals with bipolar disorder exhibit neuropsychological impairments not only during episodes of depression or mania but also when they are euthymic. One of the most consistently reported cognitive problems in euthymic individuals with bipolar disorder is impairment in episodic memory. Learning and memory depend on individuals' ability to organize information during learning. A recent study by our group showed that verbal episodic memory impairments in euthymic patients with bipolar I disorder (BP-I) are mediated by difficulties in organizing verbal information appropriately during learning. The purpose of the present study was to determine whether memory impairments in euthymic individuals with BP-I extend to non-verbal memory and whether non-verbal memory impairments are mediated by difficulties in organizing non-verbal information during encoding. METHOD: Study participants were 25 euthymic, remitted individuals with BP-I and 25 age, gender and education matched control participants. Participants completed the Rey-Osterrieth Complex Figure Test (RCFT), a well-established measure of non-verbal memory that enables assessment of organization during learning. RESULTS: Compared to control participants, BP-I participants showed impaired performance on the RCFT immediate recall. They also relied less on organizational strategies during encoding. Multiple regression modeling indicated that group differences between control and BP-I participants in long-delayed free recall did not remain statistically significant when effects of lower organization were partialled out. CONCLUSIONS: Non-verbal memory problems in individuals with bipolar disorder, while euthymic, are mediated by poor use of non-verbal organization strategies during encoding, but do not appear to reflect deficits in retention of information.

Insight into current symptoms of schizophrenia. Association with frontal cortical function and affect.

OBJECTIVE: Examine whether frontal lobe dysfunction or affective experiences correlates with lack of symptom awareness in schizophrenia. METHOD: A total of 122 consecutive adult schizophrenia outpatients were assessed cross-sectionally with standard rating scales of psychopathology and of insight, and underwent neuropsychological assessment with a battery of tests sensitive to frontal lobe dysfunction. Correlational analyses were used to determine relationships between variables. RESULTS: About 62% of patients had at least partial awareness of symptoms. Anxiety correlated modestly with insight into the abnormal nature of positive and negative symptoms. No cognitive variable was significantly correlated with symptom awareness. CONCLUSION: The pathological nature of symptoms is better recognized by patients who experience dysphoric affect. Neither severity of psychotic symptoms nor frontal lobe cognitive deficits correlates to symptom awareness. Lack of insight, which can be partial for symptoms of the illness, might be a non-reducible symptom of schizophrenia.

Bipolar depression: relationship between episode length and antidepressant treatment.

BACKGROUND: The role of antidepressant medications in bipolar depression remains controversial, mainly due to a lack of research in this area. In this study the authors examined the episode length in bipolar depression and the relationship between antidepressant therapy and episode length. METHOD: A retrospective chart review of 165 subjects identified 50 (30%) with bipolar illness who experienced a major depressive episode between 1 January 1998 and 15 December 2000. Data gathered utilized a structured instrument completed by the clinician at each visit. This instrument includes modified SCID mood modules as well as continuous ratings for each associated symptom of depression and mood elevation. Survival analysis was employed to calculate the median length of the depressive episodes for the entire group. Further survival analysis compared the episode length for subjects treated with antidepressants during the depression (N = 33) with those who did not receive antidepressants (N = 17). The rate of switch into elevated mood states was compared for the two groups. RESULTS: The survival analysis for the entire sample demonstrated 25%, 50% and 75% probability of recovery at 33 (S.E. 8.7), 66 (S.E. 17.9) and 215 (S.E. 109.9) days, respectively. Comparing those who received (N = 33) and those who did not receive (N = 17) antidepressants during the episode did not reveal any difference in the length of the depressive episode. Switch rates were not significantly different between those receiving antidepressants and those not taking these medications (15.2% v. 17.6%, respectively). CONCLUSIONS: Over the past 20 years little progress has been made in reducing the length of depressive episodes in those with bipolar illness. This is despite increasing pharmacological options available for treating depression. Clinicians treating bipolar depression should discuss with their patients the likelihood that the episode will last between 2-3 months. Our results also suggest that antidepressant treatment may not reduce the length of depressive episodes, neither did it appear to contribute to affective switch in our sample.

The Skin Picking Impact Scale (SPIS): scale development and psychometric analyses.

The Skin Picking Impact Scale (SPIS) is a self-report instrument developed to assess the psychosocial consequences of repetitive skin picking. An initial 28-item scale was administered to 31 individuals with severe self-injurious skin picking and 78 individuals with non-self-injurious skin picking. Item difficulty levels and part-whole correlations resulted in a 10-item scale with good internal consistency. SPIS scores for those with self-injurious skin picking were significantly higher than for those with non-self-injurious skin picking. SPIS scores for those with self-injurious skin picking correlated with duration of daily picking, satisfaction during picking, and shame subsequent to picking, as well as Beck Depression Inventory and Beck Anxiety Inventory scores. Sensitivity and specificity analyses indicate that a scale cutoff score of 7 optimally discriminates individuals with self-injurious skin picking from those with non-self-injurious skin picking.

The Skin Picking Scale: scale construction and psychometric analyses.

OBJECTIVE: This paper reports on the development of the Skin Picking Scale (SPS), a six-item paper-and-pencil measure for the assessment of skin picking. METHODS: 28 severe self-injurious and 77 non-self-injurious skin pickers initially completed an eight-item severity scale modeled after the Yale--Brown Obsessive--Compulsive Scale (Y-BOCS). RESULTS: Group comparisons and part--whole correlations for individual scale items resulted in a six-item scale with a total score range of 0--24. A Cronbach's alpha coefficient of.80 indicated moderate internal consistency for the scale. Construct validity was demonstrated by significant correlations between SPS total scale scores and self-reported average duration of skin picking episodes. Significant correlations were also reported between SPS total scale scores and both Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores, as well as self-reported intensity of emotions during the picking process. Lastly, sensitivity and specificity analyses suggest that a SPS cut-off score of 7 differentiates severe self-injurious and non-self-injurious skin pickers. CONCLUSION: The SPS is a valid and reliable self-report scale for the assessment of severity in medical and psychiatric patients who endorse skin picking.

Longitudinal follow-up of naturalistic treatment outcome in patients with trichotillomania.

BACKGROUND: Little is known about the longitudinal course of treatment outcome in patients with trichotillomania. The authors conducted a second follow-up assessment on a cohort of hair pullers previously studied. METHOD: Forty-four subjects completed a hair-pulling questionnaire and paper-and-pencil measures of hair-pulling severity and impact, psychosocial functioning, depression, anxiety, and self-esteem. Mean time elapsed between the first and second follow-up assessment was 2.5 years (index evaluation to first follow-up = 3.5 years). RESULTS: Twenty-seven subjects (61.4%) had active treatment since the first follow-up. No significant changes in hair pulling, depression, anxiety, or psychosocial functioning were reported from first to second follow-up. Self-esteem scores significantly worsened during this period (p = .000). A trend toward worsening also existed for psychosocial impact scores. Comparison of scores at index evaluation with second follow-up still showed significant improvement over time for hair pulling (p = .001) but significant worsening in self-esteem (p = .000). Treatment and responder status were unrelated to clinical functioning, with the exception of depression and psychosocial impact. CONCLUSION: Although hair pullers exhibit initial improvement with treatment, scale scores plateau or worsen by second follow-up. Significant worsening in self-esteem at second follow-up may be related to the absence of further improvements in hair-pulling severity. Future research should focus on the interrelationships among self-esteem, depression, and hair pulling during treatment for this disorder.

Prefrontal regions supporting spontaneous and directed application of verbal learning strategies: evidence from PET.

The prefrontal cortex has been implicated in strategic memory processes, including the ability to use semantic organizational strategies to facilitate episodic learning. An important feature of these strategies is the way they are applied in novel or ambiguous situations-failure to initiate effective strategies spontaneously in unstructured settings is a central cognitive deficit in patients with frontal lobe disorders. The current study examined strategic memory with PET and a verbal encoding paradigm that manipulated semantic organization in three encoding conditions: spontaneous, directed and unrelated. During the spontaneous condition, subjects heard 24 words that were related in four categories but presented in mixed order, and they were not informed of this structure beforehand. Any semantic reorganization was, therefore, initiated spontaneously by the subject. In the directed condition, subjects were given a different list of 24 related words and explicitly instructed to notice relationships and mentally group related words together to improve memory. The unrelated list consisted of 24 unrelated words. Behavioural measures included semantic clustering, which assessed active regrouping of words into semantic categories during free recall. In graded PET contrasts (directed > spontaneous > unrelated), two distinct activations were found in left inferior prefrontal cortex (inferior frontal gyrus) and left dorsolateral prefrontal cortex (middle frontal gyrus), corresponding to levels of semantic clustering observed in the behavioural data. Additional covariate analyses in the first spontaneous condition indicated that blood flow in orbitofrontal cortex (OFC) was strongly correlated with semantic clustering scores during immediate free recall. Thus, blood flow in OFC during encoding predicted which subjects would spontaneously initiate effective strategies during free recall. Our findings indicate that OFC performs an important, and previously unappreciated, role in strategic memory by supporting the early mobilization of effective behavioural strategies in novel or ambiguous situations. Once initiated, lateral regions of left prefrontal cortex control verbal semantic organization.

Is age at symptom onset associated with severity of memory impairment in adults with obsessive-compulsive disorder?

OBJECTIVE: Age at onset is a potentially important marker for neurobiological features of obsessive-compulsive disorder (OCD). This study examined the relationship between age at symptom onset and memory impairment in adults with OCD. METHOD: The authors used the Rey-Osterrieth Complex Figure Test and the California Verbal Learning Test to compare memory functioning of 37 adult OCD patients with self-reported childhood onset of symptoms (onset at less than 18 years of age) with that of 31 patients with adult-onset symptoms. RESULTS: No differences were found between the two groups on any of the verbal and nonverbal memory measures. CONCLUSIONS: Self-reported age at symptom onset is not associated with memory performance in adult patients with OCD according to tests previously found to be sensitive to frontal-striatal system dysfunction and impairment in OCD. Such dysfunction appears to be a consistent feature of OCD in adults, regardless of age at initial symptom onset.

Reliability and validity of a scoring system for measuring organizational approach in the Complex Figure Test.

The Rey-Osterrieth Complex Figure Test (RCFT) is a widely-used measure of visuospatial construction and nonverbal memory. One of the critical aspects of this test is that organizing the figure into meaningful perceptual units during copy enhances its subsequent free recall from memory. This study examined the psychometric properties of a new system for quantifying the organizational approach to the RCFT figure and compared it to another compatible scoring system. We investigated interrater reliability of both systems and explored the influences of copy organization and copy accuracy on immediate recall. Seventy-one participants meeting DSM-IV criteria for obsessive-compulsive disorder and 55 healthy control participants completed the copy and immediate free recall condition of the RCFT. Interrater reliability was evaluated by Kappa coefficients and Pearson correlations. The effects of copy organization and copy accuracy on immediate recall were evaluated using multiple regression analyses. Results indicated that the organizational approach could be assessed with high reliability using both scoring systems. Organization during copy was a strong predictor for subsequent free recall from memory using both approaches. Multiple regression analysis indicated that all organizational elements were not equally predictive of memory performance. This new system represents a very simple and reliable approach to scoring organization on the RCFT, since it requires the identification of only 5 figure components. These characteristics should contribute to its clinical utility.

Characteristics of memory dysfunction in body dysmorphic disorder.

Although body dysmorphic disorder (BDD) is receiving increasing empirical attention, very little is known about neuropsychological deficits in this disorder. The current study investigated the nature of memory dysfunction in BDD, including the relationship between encoding strategies and verbal and nonverbal memory performance. We evaluated 17 patients with BDD and 17 healthy controls using the Rey-Osterrieth Complex Figure Test (RCFT) and the California Verbal Learning Test (CVLT). BDD patients differed significantly from healthy controls on verbal and nonverbal learning and memory indices. Multiple regression analyses revealed that group differences in free recall were statistically mediated by deficits in organizational strategies in the BDD cohort. These findings are similar to patterns previously observed in obsessive-compulsive disorder (OCD), suggesting a potential relationship between OCD and BDD. Studies in both groups have shown that verbal and nonverbal memory deficits are affected by impaired strategic processing.

Repetitive skin-picking in a student population and comparison with a sample of self-injurious skin-pickers.

The prevalence of skin-picking and its associated characteristics were documented in a nonclinical sample of 105 college students. Subjects completed a self-report skin-picking inventory and several paper-and-pencil scales. Students who endorsed skin-picking were compared to a clinical sample of self-injurious skin-pickers (n = 31) reported on previously. Of the student subjects, 78.1% (n = 82) endorsed some degree of skin-picking and four subjects satisfied criteria for severe, self-injurious picking. Student subjects significantly differed from the clinical sample-of self-injurious skin-pickers in the duration, focus, and extent of picking, techniques used, reasons for picking, associated emotions, and picking sequelae.

Strategic processing and episodic memory impairment in obsessive compulsive disorder.

There is evidence that nonverbal memory problems in obsessive compulsive disorder (OCD) are mediated by impaired strategic processing. Although many studies have found verbal memory to be normal in OCD, these studies did not use tests designed to stress organizational strategies. This study examined verbal and nonverbal memory performance in 33 OCD patients and 30 normal control participants with the Rey-Osterrieth Complex Figure Test and the California Verbal Learning Test. OCD patients were impaired on verbal and nonverbal measures of organizational strategy and free recall. Multiple regression modeling indicated that free recall problems in OCD were mediated by impaired organizational strategies used during learning trials. Therefore, verbal and nonverbal episodic memory deficits in OCD are affected by impaired strategic processing. Results are consistent with neurobiological models proposing frontal-striatal system dysfunction in OCD.

The relationship between semantic organization and memory in obsessive-compulsive disorder.

BACKGROUND: A variety of evidence suggests that frontostriatal dysfunction is involved in obsessive-compulsive disorder (OCD). This evidence includes both neuroimaging findings and results from studies using neuropsychological assessments. Previous studies have documented nonverbal memory deficits in individuals with OCD, whereas verbal learning and memory were less affected. METHODS: The present study examined both verbal and nonverbal memory in a sample of 17 untreated outpatients with OCD. We also evaluated the effects of encoding strategies which are believed to be mediated by frontostriatal system functioning. RESULTS: OCD patients were significantly impaired in both verbal and nonverbal memory performance. This deficit was correlated with impairments in organizational and semantic clustering strategies at the time of encoding. CONCLUSIONS: Deficits in organizational strategies are consistent with frontostriatal dysfunction models in OCD.

Cognitive-behavioral therapy for depression. Applications and outcome.

This article discusses cognitive-behavioral therapy for depression, including evidence for its efficacy and how to choose between this therapy and antidepressants. The use of this therapy to prevent relapse also is presented.