Laura Bellodi

Frontal lobe dysfunction in pathological gambling patients.

BACKGROUND Limited data are available about the validity of the diagnosis of pathological gambling (PG) and about the etiology and the efficacy of different treatment strategies of this disorder; however, similarities in decision-making behavior between PG patients and patients with ventromedial prefrontal cortex lesions suggest a possible implication of these areas in the pathophysiology of this disorder, as in obsessive-compulsive disorder, in which the decision-making impairment is significantly associated with response to serotonin reuptake inhibitor treatment. Nevertheless, several studies have shown that decision-making functioning is also impaired in drug-addicted patients who have shown abnormalities in ventromedial prefrontal cortex during functional neuroimaging studies. METHODS We assessed the decision-making function mediated by the ventromedial prefrontal cortex in 20 PG patients and 40 healthy control (HC) subjects using the Gambling Task, which simulates real-life decision-making, testing the ability to balance immediate rewards against long-term negative consequence. RESULTS Significant differences were found in Gambling Task performance between HC subjects and PG patients, who showed a specific decision-making profile across the sequence of the game. The dissimilarity does not appear to depend on the basic cognitive function deficit of the PG group. CONCLUSIONS These data seem to suggest the existence of a link between PG and other disorders (i.e., obsessive-compulsive disorder and drug addiction) all having diminished ability to evaluate future consequences, which may be explained at least in part by an abnormal functioning of the orbitofrontal cortex.

Decision-making heterogeneity in obsessive-compulsive disorder: ventromedial prefrontal cortex function predicts different treatment outcomes

Certain clinical aspects of patients with Obsessive-Compulsive Disorder (OCD) appear similar to those of patients with damage to the ventromedial sector of the prefrontal cortex. The hypothesis for the involvement of the frontal region in OCD is also supported by neuropsychological findings. Building on this evidence, we assessed the performance of a group of 34 OCD patients on a measure indexing with orbitofrontal cortex functioning and compared it with the performance of two other subject groups, one consisting of 34 healthy control subjects and the other 16 patients with panic disorder. All study subjects performed a neuropsychological task, which is sensitive to frontal lobe dysfunction and simulating real-life decision-making. Significant differences were found between the neuropsychological profiles of the OCD and of other groups, pointing to a possible specificity of decision-making deficit in OCD. Comparison of the performance of the OCD patients grouped according to response to antiobsessive drug treatment showed that poor neuropsychological task performance predicted poor outcome of pharmacological treatment. Task behavior did not correlate with severity of illness or demographic characteristics of the subjects. Results support the role of the ventromedial prefrontal cortex in OCD.

Clinical predictors of drug response in obsessive-compulsive disorder.

The aim of this study was to evaluate which clinical variables might influence the antiobsessional response to proserotonergic drugs in a sample of patients with obsessive-compulsive disorder (OCD). One hundred fifty-nine patients with DSM-IV OCD underwent a 12-week standardized treatment with fluvoxamine, clomipramine, citalopram, or paroxetine. According to treatment response, defined as a reduction of the Yale-Brown Obsessive Compulsive Scale total score >35%, patients were divided into two groups. Ninety patients (56.6%) responded to treatment and 69 (43.4%) did not. Responders had a significantly higher frequency of positive family history for OCD (FH-OCD) in their first-degree relatives, whereas nonresponders had an earlier onset and a higher frequency of “poor insight” subtype and somatic obsessions. The predictive value of all these variables was tested by a stepwise logistic regression analysis that confirmed poor insight and FH-OCD to be the best predictors of poor and good drug treatment response, respectively. These preliminary findings need additional investigations toward a better definition of the genetic and biological heterogeneity of patients with OCD, and they underlie the importance of collecting the insight score and family history for psychiatric disorders in the pretreatment assessment.

Neuropsychological investigation of decision-making in anorexia nervosa

Anorexia nervosa (AN) could be considered a form of obsessive-compulsive disorder in which an impairment of the cognitive domain related to decision-making was found. We explored this function in AN patients, as well as possible differences between restricting type and binge/purge type, with the aim of examining the hypothesis that AN is part of the obsessive-compulsive spectrum. Decision-making was assessed in 59 inpatients with AN and 82 control subjects using the Gambling task, which simulates real-life decision-making by assessing the ability to balance immediate rewards against long-term negative consequences. We confirmed the supposed deficit of decision-making in AN. However, restricting and binge eating/purge subtypes showed different patterns of decision-making impairment. Poor performance on the Gambling task is not a mere consequence of starvation and does not appear to be related to illness severity. The decision-making deficiency that some AN patients show is linked to those individual features that contribute to the phenomenological expression of the disorder.

Temperament Dimensions Explain the Comorbidity of Psychiatric Disorders

The comorbidity of DSM-III-R axis I and axis II disorders presents conceptual and nosological challenges to psychiatry. In a consecutive series of 164 psychiatric outpatients and 36 healthy controls in Milan, Italy, psychopathology was measured by structured interviews for DSM-III-R disorders and temperament was measured by the Tridimensional Personality Questionnaire (TPQ). Low reward dependence (RD) distinguished cluster A personality disorders and no axis I disorders. High novelty seeking (NS) characterized cluster B personality disorders and patients with eating disorders, alcohol abuse, or substance abuse. High harm avoidance (HA) characterized all cluster C personality disorders and patients with mood or anxiety disorders. The temperament dimensions were nearly independent of one another, but patients often had multiple DSM-III-R diagnoses. The joint relations of these disorders to multiple temperament dimensions accounted for their characteristic patterns of comorbidity. These findings support the hypothesis that interactions among temperament dimensions during development influence comorbidity between axis I and axis II disorders.

In vivo PET study of 5HT2A serotonin and D2 dopamine dysfunction in drug-naive obsessive-compulsive disorder

There are several lines of evidence, the majority indirect, suggesting that changes in serotonergic or dopaminergic neurotransmission may contribute to the pathogenesis of obsessive-compulsive disorder (OCD). We evaluated the co-occurrence of serotonergic and dopaminergic dysfunctions in OCD subjects, all drug-naive, with no co-morbidity and homogeneous for symptoms. Each subject underwent two positron emission tomography (PET) scans to measure in vivo both serotonin (5-HT(2A)) and dopamine (D(2)) receptor distribution. For this, we used [11C]MDL and [11C]Raclopride, highly selective antagonists of 5-HT(2A) and D(2) receptors, respectively. The comparison with a control group was carried out using both voxel-wise (SPM2) and regions of interest (ROI) approaches. There was a significant reduction of 5-HT(2A) receptor availability in frontal polar, dorsolateral, and medial frontal cortex, as well as in parietal and temporal associative cortex of OCD patients. We also found a significant correlation between 5-HT(2A) receptor availability in orbitofrontal and dorsolateral frontal cortex and clinical severity, suggesting a specific role for serotonin in determining the OCD symptoms. There was also a significant reduction of [11C]Raclopride uptake in the whole striatum, particularly in the ventral portion, possibly reflecting endogenous dopaminergic hyperactivity. The co-existence of serotonergic and dopaminergic dysfunction in the same homogeneous group of drug-naive OCD patients provides in vivo evidence for the complex molecular mechanisms of OCD, and represents the basis for further studies on the effect of therapeutic agents with specific modulatory effects on these neurotransmission systems.

Basal-corticofrontal circuits in schizophrenia and obsessive-compulsive disorder: a controlled, double dissociation study

BACKGROUND Several lines of research suggest that prefrontal cortex dysfunctions observed in obsessive compulsive disorder (OCD) and schizophrenia (SKZ) are linked to two partially independent neuroanatomic systems: the ventromedial prefrontal cortex and the dorsolateral prefrontal cortex, with different neuroanatomic connections, including the striatum. The primary aim of this study was to test this hypothesis using a double dissociation study of neuropsychological tasks performance of the dorsolateral prefrontal cortex and ventromedial prefrontal cortex. METHODS We administered the Wisconsin Card Sorting Test, the Gambling Task, and the four-disk version of the Tower of Hanoi to 110 SKZ and 67 OCD patients and 56 control subjects. RESULTS A clear double dissociation of Wisconsin Card Sorting Test and Gambling Task performances was found, with SKZ patients performing the Wisconsin Card Sorting test significantly worse than OCD patients and control subjects and OCD patients performing the Gambling Task significantly worse than SKZ and control subjects. Both SKZ and OCD patients performed the Tower of Hanoi significantly worse than control subjects. CONCLUSIONS Results from our double dissociation study confirm the hypothesis of involvement of different frontal lobe subsystems within basal-corticofrontal circuits function in SKZ and OCD.

Carbon dioxide/oxygen challenge test in panic disorder.

The effects of a single inhalation of a 35% CO2/65% O2 gas mixture were examined in 71 patients with panic disorder with or without agoraphobia and 44 normal control subjects. Compared with the placebo condition, inhalation of air, the CO2/O2 mixture elicited a clear anxiety reaction only in panic disorder patients, who experienced a sudden rise of subjective anxiety as well as of several panic symptoms. Respiratory symptoms and the fear of dying best distinguished the patients from the control subjects. Baseline anxiety was not the key factor in explaining this differential reaction. The clinical features of panic disorder (namely, frequency of panic attacks, agoraphobia, anticipatory anxiety, and duration of illness) were not significantly related to the response to the challenge test, suggesting that CO2 reactivity might be a trait marker of panic disorder.

Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case–control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and −270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the −270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.

Functional promoter polymorphism of the human serotonin transporter: lack of association with panic disorder.

To probe the hypothesis of a role for a functionally relevant 44 bp insertion/deletion of the serotonin transporter promoter in the aetiopathogenesis of panic disorder, we determined the allele frequency of the variant in two samples (combined n = 158) of panic disorder patients (DSMIII-R) and compared it with its allele frequency in two ethnically matched control samples (combined n = 169). The fact that no difference could be observed (x 2 analysis) argues against a major role for this serotonin transporter promoter polymorphism in the aetiopathogenesis of panic disorder.