Albino J. Oliveira-Maia

From Thought to Action: How the Interplay Between Neuroscience and Phenomenology Changed Our Understanding of Obsessive-Compulsive Disorder

The understanding of obsessive-compulsive disorder (OCD) has evolved with the knowledge of behavior, the brain, and their relationship. Modern views of OCD as a neuropsychiatric disorder originated from early lesion studies, with more recent models incorporating detailed neuropsychological findings, such as perseveration in set-shifting tasks, and findings of altered brain structure and function, namely of orbitofrontal corticostriatal circuits and their limbic connections. Interestingly, as neurobiological models of OCD evolved from cortical and cognitive to sub-cortical and behavioral, the focus of OCD phenomenology also moved from thought control and contents to new concepts rooted in animal models of action control. Most recently, the proposed analogy between habitual action control and compulsive behavior has led to the hypothesis that individuals suffering from OCD may be predisposed to rely excessively on habitual rather than on goal-directed behavioral strategies. Alternatively, compulsions have been proposed to result either from hyper-valuation of certain actions and/or their outcomes, or from excessive uncertainty in the monitoring of action performance, both leading to perseveration in prepotent actions such as washing or checking. In short, the last decades have witnessed a formidable renovation in the pathophysiology, phenomenology, and even semantics, of OCD. Nevertheless, such progress is challenged by several caveats, not least psychopathological oversimplification and overgeneralization of animal to human extrapolations. Here we present an historical overview of the understanding of OCD, highlighting converging studies and trends in neuroscience, psychiatry and neuropsychology, and how they influenced current perspectives on the nosology and phenomenology of this disorder.

Hypomania induced by a Garcinia cambogia supplement

Garcinia cambogia, a tropical fruit traditionally used in India and Southeast Asia for culinary and therapeutic purposes, recently became a popular ingredient in weight-loss over-thecounter supplements. Hydroxycitric acid, considered its main active ingredient, has serotoninergic effects and has been implicated in cases of severe serotoninergic syndrome. Such effects have been proposed to underlie the occurrence of mania associated with consumption of supplements containing Garcinia (Hendrickson et al., 2016; Narasimha et al., 2013). Here, we present the case of a 51-year-old woman with a 12-year history of type 1 bipolar disorder. Written informed consent was obtained from the patient for publication of patient information. After introduction of mood stabilizers, the patient remained stable, with only occasional episodes of hypomania or mild depression. After 2 years of full stability, under treatment with valproic acid 1250 mg/day and paroxetine 20 mg/day, the patient started consumption of a weight-loss dietary supplement containing Garcinia cambogia, calcium, chromium and potassium. After 2 weeks, irritability, agitation, increased energy and decreased need for sleep were noticed, that were sustained until the next routine visit with the psychiatrist, which was 2 weeks later. Given the assessment of a hypomanic episode temporally related to consumption of the dietary supplement, and considering the available literature (Hendrickson et al., 2016; Narasimha et al., 2013), the patient was advised to discontinue the supplement, while maintaining other medication. She returned 2 weeks later and reported that approximately 1 week after ceasing the supplement, while maintaining treatment with valproic acid and paroxetine at the same doses, her mood had stabilized with full remission of all symptoms of hypomania. We believe this case supports and extends prior reports of Garciniaassociated mania. Critically, prior reports either omitted full supplement composition (Hendrickson et al., 2016) or reported on mania after consumption of a supplement containing also other active stimulants, such as caffeine and guarana (Narasimha et al., 2013), rather than only Garcinia and inert ingredients, as reported here. Furthermore, in previous cases, treatment included introduction of mood stabilizers, neuroleptics and/or benzodiazepines, such that improvement could not be attributed specifically to withdrawal of the supplement (Hendrickson et al., 2016; Narasimha et al., 2013). Here, improvement of manic symptoms resulted only from withdrawal of Garcinia, meriting an assessment of a probable/likely causal association between consumption of the Garcinia supplement and occurrence of hypomania (Edwards and Aronson, 2000). This case thus underscores the need to explore and record use of dietary supplements in patients with bipolar disorder, while reinforcing the adequacy of recommending against the use of Garcinia supplement in this patient population.

The Mental Health Recovery Measure can be used to assess aspects of both customer-based and service-based recovery in the context of severe mental illness

Within clinical psychiatry, recovery from severe mental illness (SMI) has classically been defined according to symptoms and function (service-based recovery). However, service-users have argued that recovery should be defined as the process of overcoming mental illness, regaining self-control and establishing a meaningful life (customer-based recovery). Here, we aimed to compare customer-based and service-based recovery and clarify their differential relationship with other constructs, namely needs and quality of life. The study was conducted in 101 patients suffering from SMI, recruited from a rural community mental health setting in Portugal. Customer-based recovery and function-related service-based recovery were assessed, respectively, using a shortened version of the Mental Health Recovery Measure (MHRM-20) and the Global Assessment of Functioning score. The Camberwell Assessment of Need scale was used to objectively assess needs, while subjective quality of life was measured with the TL-30s scale. Using multiple linear regression models, we found that the Global Assessment of Functioning score was incrementally predictive of the MHRM-20 score, when added to a model including only clinical and demographic factors, and that this model was further incremented by the score for quality of life. However, in an alternate model using the Global Assessment of Functioning score as the dependent variable, while the MHRM-20 score contributed significantly to the model when added to clinical and demographic factors, the model was not incremented by the score for quality of life. These results suggest that, while a more global concept of recovery from SMI may be assessed using measures for service-based and customer-based recovery, the latter, namely the MHRM-20, also provides information about subjective well-being. Pending confirmation of these findings in other populations, this instrument could thus be useful for comprehensive assessment of recovery and subjective well-being in patients suffering from SMI.

Brain-derived neurotrophic factor: a biomarker for obsessive-compulsive disorder?

Suliman et al. (2013) have performed a meta-analysis of studies comparing brain-derived neurotrophic factor (BDNF) levels between patients with anxiety disorders and healthy controls. BDNF is initially synthesized as a precursor (pre-pro-BDNF) that is sequentially cleaved into BDNF (Reichardt, 2006). It acts on the TRKB receptor, promoting cellular proliferation, survival and differentiation (Chao, 2003), and is considered to be an important mediator of enduring experience-dependent changes in the brain (Park and Poo, 2013). Furthermore, BDNF and/or other neurotrophic factors may be reduced in disorders such as depression (Duman and Monteggia, 2006), as has been proposed due to the presence of reduced hippocampal volume in depressed patients (Sheline et al., 1996). Thus, there has been much interest in verifying if, across multiple psychiatric disorders, including anxiety disorders, BDNF can be used as a biomarker. Suliman et al. (2013) have synthesized findings in from 8 studies, with a total of 1179 participants, and their findings suggest that BDNF levels are reduced in individuals with anxiety disorders. However, the authors also found that this effect is largely explained by findings in patients with obsessive-compulsive disorder (OCD).

Association between hedonic hunger and body-mass index versus obesity status

Obesity-associated differences in hedonic hunger, while consistently reported, have not been adequately quantified, with most studies failing to demonstrate strong correlations between Body Mass Index (BMI) and hedonic hunger indicators. Here, we quantified and assessed the nature of the relationship between hedonic hunger and BMI, in a cross-sectional study using the Portuguese version of the PFS (P-PFS) to measure hedonic hunger. Data were collected from 1266 participants belonging to non-clinical, clinical (candidates for weight-loss surgery) and population samples. Across samples, significant but weak positive associations were found between P-PFS scores and BMI, in adjusted linear regression models. However, in logistic regression models of data from the clinical and non-clinical samples, the P-PFS Food Available domain score was significantly and robustly associated with belonging to the clinical sample (OR = 1.8, 95%CI: 1.2–2.8; p = 0.008), while in the population sample it was associated to being obese (OR = 2.1, 95%CI: 1.6–2.7; p < 0.001). Thus, hedonic hunger levels are associated with obesity status with the odds of being obese approximately doubling for each unit increase in the P-PFS Food Available score.

Repetitive Transcranial Magnetic Stimulation for Treatment of Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting as lifelong deficits in social communication and interaction, as well as restricted repetitive behaviors, interests and activities. While there are no specific pharmacological or other physical treatments for autism, in recent years repetitive Transcranial Magnetic Stimulation (rTMS), a technique for non-invasive neuromodulation, has attracted interest due to potential therapeutic value. Here we report the results of a systematic literature review and meta-analysis on the use of rTMS to treat ASD. Methods: We performed a systematic literature search on PubMed, Web of Science, Science Direct, Bielefeld Academic Search, and Educational Resources Information Clearinghouse. Search terms reflected diagnoses and treatment modalities of interest. Studies reporting use of rTMS to treat core ASD or cognitive symptoms in ASD were eligible. Two researchers performed article selection and data extraction independently, according to PRISMA guidelines. Changes in ASD clinical scores or in cognitive performance were the main outcomes. Random effects meta-analysis models were performed. Results: We found 23 eligible reports, comprising 4 case-reports, 7 non-controlled clinical trials, and 12 controlled clinical trials, comparing the effects of real TMS with waiting-list controls (n = 6) or sham-treatment (n = 6). Meta-analyses showed a significant, but moderate, effect on repetitive and stereotyped behaviors, social behavior, and number of errors in executive function tasks, but not other outcomes. Most studies had a moderate to high risk of bias, mostly due to lack of subject- and evaluator-blinding to treatment allocation. Only 5 studies reported stability of these gains for periods of up 6 months, with descriptions that improvements were sustained over time. Conclusions: Existing evidence supports that TMS could be useful to treat some dimensions of ASD. However, such evidence must be regarded with care, as most studies did not adequately control for placebo effects. Moreover, little is known regarding the most effective stimulation parameters, targets, and schedules. There is an urgent need for further randomized, double-blind, sham-controlled trials, with adequate follow-up periods, to test the efficacy of transcranial magnetic stimulation to treat these disorders. Available evidence must be regarded as preliminary and insufficient, at present, to support offering TMS to treat ASD.

Right-sided brain lesions predominate among patients with lesional mania: evidence from a systematic review and pooled lesion analysis

Background Despite claims that lesional mania is associated with right-hemisphere lesions, supporting evidence is scarce, and association with specific brain areas has not been demonstrated. Aims To test whether focal brain lesions in lesional mania are more often right-than left-sided, and if lesions converge on areas relevant to mood regulation. Methods We performed a systematic literature search (PROSPERO registration CRD42016053675) on PubMed and Web-Of-Science, using terms that reflected diagnoses and structures of interest, and lesional mechanisms. Two researchers reviewed the articles separately according to PRISMA Guidelines, to select reports of adult-onset hypomania, mania or mixed state following a focal brain lesion. When available, eligible lesion images were manually traced onto the corresponding slices of MNI space, and lesion topography analyzed using standard brain atlases. Pooled-analyses of individual patient data were performed. Results Data from 207 lesional mania patients was extracted from 110 reports. Among patients with focal lesions (N=197) more patients had lesions involving the right (84.3%) than the left (34.5%) hemisphere. Among 54 lesion images that were available, right-sided predominance of lesions was confirmed, and found to be was conserved across multiple brain regions, including the temporal lobe, fusiform gyrus and thalamus. These, in addition to several frontal lobe areas, were also identified as preferential lesion sites in comparisons with control lesions. Conclusions Pooled-analyses, based on the most comprehensive dataset of lesional mania available to date, confirm a preferential association with right-hemisphere lesions, while suggesting that several brain areas/circuits, relevant to mood regulation, are most frequently affected.

Criterion Validity of the Yale-Brown Obsessive-Compulsive Scale Second Edition for Diagnosis of Obsessive-Compulsive Disorder in Adults

Background: While the Yale-Brown Obsessive-Compulsive Scale Second Edition (Y-BOCS-II) is the gold-standard for measurement of obsessive-compulsive (OC) symptom severity, its factor structure is still a matter of debate and, most importantly, criterion validity for diagnosis of OC disorder (OCD) has not been tested. This study aimed to clarify factor structure and criterion validity of the Y-BOCS-II. Methods: We first validated and quantified the psychometric properties of a culturally adapted Portuguese translation of the Y-BOCS-II (PY-BOCS-II). The PY-BOCS-II and other psychometric instruments, including the OCD subscale of the Structured Clinical Interview for the DSM-IV, used to define OCD diagnosis, were administered to 187 participants (52 patients with OCD, 18 with other mood and anxiety disorders and 117 healthy subjects). In a subsample of 20 OCD patients and the 18 patients with other diagnoses, PY-BOCS-II was applied by clinicians blinded to diagnosis. Results: PY-BOCS-II had excellent internal consistency (Cronbachs α = 0.96) and very good test-retest reliability (Pearsons r = 0.94). Exploratory factor analysis revealed a two-factor structure with loadings consistent with the Obsessions and Compulsions subscales, and there was good to acceptable convergent and divergent validity. Importantly, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve suggested elevated accuracy in discriminating between patients with OCD and control subjects (AUC = 0.96; 95% confidence interval [CI]: 0.92-0.99), that was retained in comparisons with age, gender and education matched controls (AUC = 0.95; 95% CI: 0.91-0.99), as well as with patients with other mood and anxiety disorders (AUC = 0.93; 95% CI: 0.84-1). Additionally, a cut-off score of 13 had optimal discriminatory ability for the diagnosis of OCD, with sensitivity ranging between 85 and 90%, and specificity between 94 and 97%, respectively when all samples or only the clinical samples were considered. Conclusion: The PY-BOCS-II has excellent psychometric properties to assess the severity of obsessive-compulsive symptoms, reflecting obsessive, and compulsive dimensions, compatible with currently defined subscales. Furthermore, we found that a cut-off of 13 for the Y-BOCS-II total score has good to excellent sensitivity and specificity for the diagnosis of OCD.

Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systematic review and meta-analysis

BACKGROUND The therapeutic options for treatment-resistant depression (TRD) encompass a range of neuromodulatory techniques, including repetitive transcranial magnetic stimulation (rTMS). While rTMS is safe and has documented short-term efficacy, durability of antidepressant effects is poorly established. OBJECTIVE Assess existing evidence regarding durability of rTMS-induced antidepressant response. METHODS We performed a systematic review of studies reporting antidepressant outcome measures collected three or more months after the end of an induction course of rTMS for depression. Among responders to the induction course, we used a meta-analytic approach to assess response rates at 3 (m3), 6 (m6) or 12 (m12) months after induction, and studied predictors of responder rates using meta-regression. RESULTS Nineteen studies published between 2002 and 2018 were included. Eighteen were eligible for analysis at m3 (732 patients) and m6 (695 patients) and 9 at m12 (247 patients). Among initial responders, 66.5% sustained response at m3 (95% CI = 57.1-74.8%, I2 = 27.6%), 52.9% at m6 (95% CI = 40.3-65%, I2 = 0%), and 46.3% at m12 (95% CI = 32.6-60.7%, I2 = 0%), in the absence of any major bias. Random-effects meta-regressions further demonstrated that a higher proportion of women, as well as receipt of maintenance treatment, predicted higher responder rates at specific time-points. CONCLUSIONS rTMS is a durable treatment for depression, with sustained responder rates of 50% up to 1 year after a successful induction course of treatment. Maintenance treatment may enhance the durability of the antidepressant effects of rTMS, and should be considered in clinical practice, as well as systematically explored in future clinical trials.

34 A lesion map of secondary bipolar disorder

Objective Bipolar Disorder (BPD) is a severe mood disorder, affecting 1.5%–4.4% of the population, and manifesting as an episodic, recurrent disturbance of mood, sleep, and behaviour. Secondary BPD (SBPD) develops following a brain insult, and is traditionally associated with right frontal lobe lesions. Yet, evidence supporting this association is mostly anecdotal. Here, we use two methodologies to study the neuroanatomy of SBPD: a systematic review of SBPD cases published in the literature, and reconstitution of brain lesions from a cohort of patients with SBPD in a single 3D template brain. Method Systematic search of pubmed and WebOfScience for SBPD. For the lesion-map, data were collected from 16 consecutive patients (6 women, 10 men, mean age 60,75±14,27 years) with SBPD developing after an MRI-documented right-sided brain-lesion. For each scan we selected the sequence (T1, T2, or FLAIR) providing the best lesion discrimination. Lesions were manually segmented using MITK software.1 After segmentation, each scan was co-registered onto a template reference brain2 using 3DSlicer software.3 Co-registration applies a transformation vector along the three axes of the source image, such that its voxels match the reference brain voxels to the highest possible degree. The resulting transformation vector was then applied to the image of each segmented lesion, and all the co-registered lesions were overlapped on the template brain scan (Automated anatomical labelling atlas or John Hopkins University white matter tractography Atlas for gray- and white-matter analysis, respectively). Results 1476 articles were found in literature review, with 207 eligible cases, including 193 with focal brain lesions, mostly right-sided (84.5%) and more rarely left-sided (34.7%). Lesions were overrepresented in the frontal and temporal lobes bilaterally. In the 3D lesion-map, lesions were spread over the right hemisphere, with highest overlap in a medial area of the superior frontal gyrus (6 patients). Grey-matter quantitative mapping showed that the right superior frontal gyrus right anterior cingulate and supramarginal gyrus and right insula were lesioned in the highest number of patients (respectively 8, 7 and 6 patients). White-matter analysis highlighted the right superior longitudinal fasciculus and superior corona radiata (6 patients each), anterior corona radiata and body of corpus callosum (5 patients each). Conclusion Our systematic review confirmed that right-sided frontotemporal lesions predominate in SBPD. In our cohort lesions converged on areas of the right executive control and anterior salience networks. Both have been implicated in the neurophysiology of primary BPD.4,5