Linking Cognitive Integrity to Working Memory Dynamics in the Aging Human Brain.

Aging is accompanied by a decline of working memory, an important cognitive capacity that involves stimulus-selective neural activity that persists after stimulus presentation. Here, we unraveled working memory dynamics in older human adults (male and female) including those diagnosed with mild cognitive impairment (MCI) using a combination of behavioral modeling, neuropsychological assessment, and MEG recordings of brain activity. Younger adults (male and female) were studied with behavioral modeling only. Participants performed a visuospatial delayed match-to-sample task under systematic manipulation of the delay and distance between sample and test stimuli. Their behavior (match/nonmatch decisions) was fit with a computational model permitting the dissociation of noise in the internal operations underlying the working memory performance from a strategic decision threshold. Task accuracy decreased with delay duration and sample/test proximity. When sample/test distances were small, older adults committed more false alarms than younger adults. The computational model explained the participants' behavior well. The model parameters reflecting internal noise (not decision threshold) correlated with the precision of stimulus-selective cortical activity measured with MEG during the delay interval. The model uncovered an increase specifically in working memory noise in older compared with younger participants. Furthermore, in the MCI group, but not in the older healthy controls, internal noise correlated with the participants' clinically assessed cognitive integrity. Our results are consistent with the idea that the stability of working memory contents deteriorates in aging, in a manner that is specifically linked to the overall cognitive integrity of individuals diagnosed with MCI.

Dopamine D2/3 receptor availability in alcohol use disorder and individuals at high risk: Towards a dimensional approach.

Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine-related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying 18 F-fallypride positron emission tomography (18 F-PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low-risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.

Neuropsychosocial profiles of current and future adolescent alcohol misusers.

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

Heavy drinking in adolescents is associated with change in brainstem microstructure and reward sensitivity.

Heavy drinker adolescents: altered brainstem microstructure.

The cortical-cerebellar circuit is vulnerable to heavy drinking (HD) in adults. We hypothesized early microstructural modifications of the pons/midbrain region, containing core structures of the reward system, in HD adolescents. Thirty-two otherwise symptom-free HDs at age 14 (HD14) and 24 abstainers becoming HDs at age 16 (HD16) were identified in the community with the Alcohol Use Disorders Identification Test (AUDIT) and compared with abstainers. The monetary incentive delay (MID) task assessed reward-sensitive performance. Voxelwise statistics of diffusion tensor imaging (DTI) values in the thalamo-ponto-mesencephalic region were obtained using tract-based spatial statistics. Projections between the ventral tegmental area (VTA) and the nucleus accumbens (NAcc) were identified by probabilistic tractography. Lower fraction of anisotropy and higher radial diffusivity (RD) values were detected in the upper dorsal pons of HD14 adolescents, and a trend for higher RD in HD16, compared with abstainers. When expecting reward, HD14 had higher MID task success scores than abstainers, and success scores were higher with a lower number of tracts in all adolescents. In symptom-free community adolescents, a region of lower white matter (WM) integrity in the pons at age 14 was associated with current HD and predicted HD at age 16. HD was related to reward sensitivity.

Modulation of orbitofrontal-striatal reward activity by dopaminergic functional polymorphisms contributes to a predisposition to alcohol misuse in early adolescence.

BACKGROUND: Abnormalities in reward circuit function are considered a core feature of addiction. Yet, it is still largely unknown whether these abnormalities stem from chronic drug use, a genetic predisposition, or both. METHODS: In the present study, we investigated this issue using a large sample of adolescent children by applying structural equation modeling to examine the effects of several dopaminergic polymorphisms of the D1 and D2 receptor type on the reward function of the ventral striatum (VS) and orbital frontal cortex (OFC), and whether this relationship predicted the propensity to engage in early alcohol misuse behaviors at 14 years of age and again at 16 years of age. RESULTS: The results demonstrated a regional specificity with which the functional polymorphism rs686 of the D1 dopamine receptor (DRD1) gene and Taq1A of the ANKK1 gene influenced medial and lateral OFC activation during reward anticipation, respectively. Importantly, our path model revealed a significant indirect relationship between the rs686 of the DRD1 gene and early onset of alcohol misuse through a medial OFC × VS interaction. CONCLUSIONS: These findings highlight the role of D1 and D2 in adjusting reward-related activations within the mesocorticolimbic circuitry, as well as in the susceptibility to early onset of alcohol misuse.

Separate neural systems for behavioral change and for emotional responses to failure during behavioral inhibition.

To analyze the involvement of different brain regions in behavioral inhibition and impulsiveness, differences in activation were investigated in fMRI data from a response inhibition task, the stop-signal task, in 1709 participants. First, areas activated more in stop-success (SS) than stop-failure (SF) included the lateral orbitofrontal cortex (OFC) extending into the inferior frontal gyrus (ventrolateral prefrontal cortex, BA 47/12), and the dorsolateral prefrontal cortex (DLPFC). Second, the anterior cingulate and anterior insula (AI) were activated more on failure trials, specifically in SF versus SS. The interaction between brain region and SS versus SF activations was significant (P = 5.6 * 10-8 ). The results provide new evidence from this "big data" investigation consistent with the hypotheses that the lateral OFC is involved in the stop-related processing that inhibits the action; that the DLPFC is involved in attentional processes that influence task performance; and that the AI and anterior cingulate are involved in emotional processes when failure occurs. The investigation thus emphasizes the role of the human lateral OFC BA 47/12 in changing behavior, and inhibiting behavior when necessary. A very similar area in BA47/12 is involved in changing behavior when an expected reward is not obtained, and has been shown to have high functional connectivity in depression. Hum Brain Mapp 38:3527-3537, 2017. © 2017 Wiley Periodicals, Inc.

Global genetic variations predict brain response to faces.

Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼ 500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40-50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R(2) = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R(2) = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.

Structural brain correlates of adolescent resilience.

BACKGROUND: Despite calls for integration of neurobiological methods into research on youth resilience (high competence despite high adversity), we know little about structural brain correlates of resilient functioning. The aim of the current study was to test for brain regions uniquely associated with positive functioning in the context of adversity, using detailed phenotypic classification. METHODS: 1,870 European adolescents (Mage  = 14.56 years, SDage  = 0.44 years, 51.5% female) underwent MRI scanning and completed behavioral and psychological measures of stressful life events, academic competence, social competence, rule-abiding conduct, personality, and alcohol use. RESULTS: The interaction of competence and adversity identified two regions centered on the right middle and superior frontal gyri; grey matter volumes in these regions were larger in adolescents experiencing adversity who showed positive adaptation. Differences in these regions among competence/adversity subgroups were maintained after controlling for several covariates and were robust to alternative operationalization decisions for key constructs. CONCLUSIONS: We demonstrate structural brain correlates of adolescent resilience, and suggest that right prefrontal structures are implicated in adaptive functioning for youth who have experienced adversity.

New evidence of factor structure and measurement invariance of the SDQ across five European nations.

The main purpose of the present study was to analyse the internal structure and to test the measurement invariance of the Strengths and Difficulties Questionnaire (SDQ), self-reported version, in five European countries. The sample consisted of 3012 adolescents aged between 12 and 17 years (M = 14.20; SD = 0.83). The five-factor model (with correlated errors added), and the five-factor model (with correlated errors added) with the reverse-worded items allowed to cross-load on the Prosocial subscale, displayed adequate goodness of-fit indices. Multi-group confirmatory factor analysis showed that the five-factor model (with correlated errors added) had partial strong measurement invariance by countries. A total of 11 of the 25 items were non-invariant across samples. The level of internal consistency of the Total difficulties score was 0.84, ranging between 0.69 and 0.78 for the SDQ subscales. The findings indicate that the SDQ's subscales need to be modified in various ways for screening emotional and behavioural problems in the five European countries that were analysed.

Dimensions of manic symptoms in youth: psychosocial impairment and cognitive performance in the IMAGEN sample.

BACKGROUND: It has been reported that mania may be associated with superior cognitive performance. In this study, we test the hypothesis that manic symptoms in youth separate along two correlated dimensions and that a symptom constellation of high energy and cheerfulness is associated with superior cognitive performance. METHOD: We studied 1755 participants of the IMAGEN study, of average age 14.4 years (SD = 0.43), 50.7% girls. Manic symptoms were assessed using the Development and Wellbeing Assessment by interviewing parents and young people. Cognition was assessed using the Wechsler Intelligence Scale For Children (WISC-IV) and a response inhibition task. RESULTS: Manic symptoms in youth formed two correlated dimensions: one termed exuberance, characterized by high energy and cheerfulness and one of undercontrol with distractibility, irritability and risk-taking behavior. Only the undercontrol, but not the exuberant dimension, was independently associated with measures of psychosocial impairment. In multivariate regression models, the exuberant, but not the undercontrolled, dimension was positively and significantly associated with verbal IQ by both parent- and self-report; conversely, the undercontrolled, but not the exuberant, dimension was associated with poor performance in a response inhibition task. CONCLUSIONS: Our findings suggest that manic symptoms in youth may form dimensions with distinct correlates. The results are in keeping with previous findings about superior performance associated with mania. Further research is required to study etiological differences between these symptom dimensions and their implications for clinical practice.

Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans.

Oxytocin (OT) is becoming increasingly established as a prosocial neuropeptide in humans with therapeutic potential in treatment of social, cognitive, and mood disorders. However, the potential of OT as a general facilitator of human learning and empathy is unclear. The current double-blind experiments on healthy adult male volunteers investigated first whether treatment with intranasal OT enhanced learning performance on a feedback-guided item-category association task where either social (smiling and angry faces) or nonsocial (green and red lights) reinforcers were used, and second whether it increased either cognitive or emotional empathy measured by the Multifaceted Empathy Test. Further experiments investigated whether OT-sensitive behavioral components required a normal functional amygdala. Results in control groups showed that learning performance was improved when social rather than nonsocial reinforcement was used. Intranasal OT potentiated this social reinforcement advantage and greatly increased emotional, but not cognitive, empathy in response to both positive and negative valence stimuli. Interestingly, after OT treatment, emotional empathy responses in men were raised to levels similar to those found in untreated women. Two patients with selective bilateral damage to the amygdala (monozygotic twins with congenital Urbach-Wiethe disease) were impaired on both OT-sensitive aspects of these learning and empathy tasks, but performed normally on nonsocially reinforced learning and cognitive empathy. Overall these findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men.

Altered awareness of action in schizophrenia: a specific deficit in predicting action consequences.

Patients suffering from schizophrenia may report unusual experiences of their own actions. They may either feel that external forces are controlling their actions or even their thoughts, or they may feel in control of events that in fact are not caused by their actions. Most theories link these disturbances in the sense of agency to deficits in motor prediction, resulting in a mismatch between predicted and actual sensory feedback at a central comparator mechanism. Such theories therefore can account for situations in which the sense of agency is reduced. However, other experiments as well as clinical observations show an enhanced rather than reduced sense of agency in schizophrenic patients. Here, we distinguish between a predictive and a retrospective mechanism where both contribute to the experience of agency, and show that schizophrenia is associated with a specific impairment to the predictive component. We measured subjective time estimates of self-initiated voluntary action (a key press) that were followed by a sensory effect (a tone). When the voluntary actions had a high probability of causing tones, healthy volunteers showed a predictive shift of the perceptual estimate of the action towards the tone, even on occasional trials where the tone was omitted. No such shift occurred in the absence of the tone on blocks when tones were less frequent. The predictive component of action awareness was calculated as the difference between time estimates on 'action only' trials from blocks with lower and higher tone probabilities. Schizophrenic patients lacked this predictive component of action awareness, showing a shift on 'action only' trials, regardless of the probability of the tone. Importantly, the schizophrenic deficit in predicting the relation between action and effect was strongly correlated with severity of positive psychotic symptoms, specifically delusions and hallucinations. Furthermore, the patients showed an exaggerated retrospective binding between action and tone, shifting the perceived time of action whenever the tone occurred, relative to when it did not occur. Our quantitative, implicit measures show how basic sensory and motor experience may be altered in acute psychosis. The enhanced sense of agency in schizophrenia reflects reliance on retrospection, rather than prediction, to associate actions with external events. The failure to predict the effects of one's own actions may underlie the blurring and confusion in the relationship between the self and the world that characterizes acute psychosis.

Altered sense of agency in schizophrenia and the putative psychotic prodrome.

The mechanisms underlying distortions in sense of agency, i.e. the experience of controlling one's own actions and their consequences, in schizophrenia are not fully understood and have barely been investigated in patients classified as being in a putative psychotic prodrome. This study aims to expound the contribution of early and late illness-related processes. Thirty schizophrenia patients, 30 putatively prodromal patients and 30 healthy controls were instructed to reproduce a computer-generated series of drum sounds on a drum pad. While tapping, subjects heard either their self-produced tones or a computer-controlled reproduction of the drum tone series that used either exactly the same, an accelerated or decelerated tempo. Subjects had to determine the source of agency. Results show similar significant impairments in assigning the source of agency under ambiguous conditions in schizophrenia and putatively prodromal patients and an exaggerated self-attribution bias, both of which were significantly correlated with increased (ego-)psychopathology. Patient groups, however, benefited significantly more than controls from additional sensorimotor cues to agency. Sensorimotor input seems to be a compensatory mechanism involved in correctly attributing agency. We deduce that altered awareness of agency may hold promise as an additional risk factor for psychosis.

The "VIP-ADHD trial": Does brain arousal have prognostic value for predicting response to psychostimulants in adult ADHD patients?

EEG studies have shown that adult ADHD patients have less stable brain arousal regulation than age and gender matched controls. Psychostimulants have brain arousal stabilising properties evident in EEG patterns. The aim of this study was to investigate whether the stability of brain arousal regulation has prognostic value in predicting response to methylphenidate therapy in adult ADHD patients. In an open-label, single-arm, multi-centre, confirmatory trial, 121 adult ADHD patients were recruited and 112 qualified for the full analysis set. All participants received an initial dose of 20 mg extended release methylphenidate at baseline. After a titration phase of up to 4 weeks, patients remained on a weight-based target dose of extended release methylphenidate for 4 weeks. Using the Vigilance Algorithm Leipzig (VIGALL 2.1), we assessed brain arousal regulation before the treatment with methylphenidate, based on a 15-min EEG at quiet rest recorded at baseline. Using automatic stage-classification of 1 s segments, we computed the mean EEG-vigilance (indexing arousal level) and an arousal stability score (indexing arousal regulation). The primary endpoint was the association between successful therapy, defined by a 30% reduction in CAARS, and stable/unstable brain arousal. 52 patients (46%) showed an unstable brain arousal regulation of which 23% had therapy success. In the stable group, 35% had therapy success, implying an absolute difference of 12 percentage points (95% CI -5 to 29, p = 0.17) in the direction opposite to the hypothesized one. There were no new findings regarding the tolerability and safety of extended release methylphenidate therapy.

Pubertal maturation and sex effects on the default-mode network connectivity implicated in mood dysregulation.

This study examines the effects of puberty and sex on the intrinsic functional connectivity (iFC) of brain networks, with a focus on the default-mode network (DMN). Consistently implicated in depressive disorders, the DMN's function may interact with puberty and sex in the development of these disorders, whose onsets peak in adolescence, and which show strong sex disproportionality (females > males). The main question concerns how the DMN evolves with puberty as a function of sex. These effects are expected to involve within- and between-network iFC, particularly, the salience and the central-executive networks, consistent with the Triple-Network Model. Resting-state scans of an adolescent community sample (n = 304, male/female: 157/147; mean/std age: 14.6/0.41 years), from the IMAGEN database, were analyzed using the AFNI software suite and a data reduction strategy for the effects of puberty and sex. Three midline regions (medial prefrontal, pregenual anterior cingulate, and posterior cingulate), within the DMN and consistently implicated in mood disorders, were selected as seeds. Within- and between-network clusters of the DMN iFC changed with pubertal maturation differently in boys and girls (puberty-X-sex). Specifically, pubertal maturation predicted weaker iFC in girls and stronger iFC in boys. Finally, iFC was stronger in boys than girls independently of puberty. Brain-behavior associations indicated that lower connectivity of the anterior cingulate seed predicted higher internalizing symptoms at 2-year follow-up. In conclusion, weaker iFC of the anterior DMN may signal disconnections among circuits supporting mood regulation, conferring risk for internalizing disorders.

Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: no effects on brain-derived neurotrophic factor (BDNF) concentrations in serum.

BACKGROUND: Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex is a brain stimulation technique widely used to treat depression. BDNF serum concentrations have been shown to be decreased in patients with major depressive disorder and can be upregulated by several antidepressive treatment strategies including repetitive TMS. METHODS: In this study we were interested whether acute TMS evolves effects on serum BDNF concentrations in 42 healthy volunteers. RESULTS: Mean BDNF serum concentration in 19 male and 23 female volunteers was 10.70+/-3.6 ng/ml (n=42) at baseline, and 10.76+/-3.9 ng/ml (n=42) after TMS treatment. BDNF serum levels did not change after acute TMS (n=42, Z=-0.44, p=0.965). BDNF serum concentrations at baseline did not differ between male (n=19, 10.05+/-2.6 ng/ml) and female (n=23, 11.25+/-4.27 ng/ml) participants of the study (n=42, Z=-0.91, p=0.363). CONCLUSIONS: Our result suggests that TMS does not change BDNF serum concentrations immediately in healthy human volunteers.

Early Variations in White Matter Microstructure and Depression Outcome in Adolescents With Subthreshold Depression.

OBJECTIVE: White matter microstructure alterations have recently been associated with depressive episodes during adolescence, but it is unknown whether they predate depression. The authors investigated whether subthreshold depression in adolescence is associated with white matter microstructure variations and whether they relate to depression outcome. METHOD: Adolescents with subthreshold depression (N=96) and healthy control subjects (N=336) drawn from a community-based cohort were compared using diffusion tensor imaging and whole brain tract-based spatial statistics (TBSS) at age 14 to assess white matter microstructure. They were followed up at age 16 to assess depression. Probabilistic tractography was used to reconstruct white matter streamlines spreading from the regions identified in the TBSS analysis and along bundles implicated in emotion regulation, the uncinate fasciculus and the cingulum. The authors searched for mediating effects of white matter microstructure on the relationship between baseline subthreshold depression and depression at follow-up, and then explored the specificity of the findings. RESULTS: Lower fractional anisotropy (FA) and higher radial diffusivity were found in the anterior corpus callosum in the adolescents with subthreshold depression. Tractography analysis showed that they also had lower FA in the right cingulum streamlines, along with lower FA and higher mean diffusivity in tracts connecting the corpus callosum to the anterior cingulate cortex. The relation between subthreshold depression at baseline and depression at follow-up was mediated by FA values in the latter tracts, and lower FA values in those tracts distinctively predicted higher individual risk for depression. CONCLUSIONS: Early FA variations in tracts projecting from the corpus callosum to the anterior cingulate cortex may denote a higher risk of transition to depression in adolescents.

Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) signaling at synapses improves synaptic strengthening associated with learning and memory. In the present study we hypothesized that serum BDNF concentration is associated with in vivo level of cerebral N-acetylaspartate (NAA), a well established marker of neuronal integrity. METHODS: In 36 healthy subjects BDNF serum concentration and absolute concentration of NAA together with other metabolites were measured by proton magnetic resonance spectroscopy (1H-MRS) in regions with high BDNF levels (anterior cingulate cortex [ACC], left hippocampus). Relationship between BDNF concentration and brain metabolites was studied in linear regression analysis with BDNF concentration as dependent variable and metabolite concentrations, age, and gender as predictor variables. RESULTS: The BDNF serum concentrations were positively associated with the concentrations of NAA (T = 2.193, p = .037) and total choline (T = 1.997, p = .055; trend) but not total creatine or glutamate in the ACC. No significant association was observed between BDNF serum concentration and absolute metabolite concentrations in the hippocampus. CONCLUSIONS: The preliminary data might indicate that BDNF serum concentration reflects some aspects of neuronal plasticity as indicated by its association with NAA level in the cerebral cortex. The results would be in line with the notion that BDNF plays a central role in the regulation of neuronal survival and differentiation in the human brain.

Gender-dependent association of the functional catechol-O-methyltransferase Val158Met genotype with sensation seeking personality trait.

The gene encoding cathechol-O-methyltransferase (COMT) contains a common functional missense polymorphism (Val158Met) that regulates dopamine in an allele-dependent manner. A pivotal role of dopamine neurotransmission in the prefrontal cortex has been implicated in drug-seeking behavior and related personality traits, such as sensation seeking, with some evidence for a gender-specific association. Here, we tested the hypothesis that the COMT Val158Met polymorphism modulates the personality dimension, sensation seeking, in a gender-dependent manner. Study sample included 214 male (age 38.1+/-12.6 years) and 218 female (age 36.1+/-13.6 years) healthy volunteers, who were assessed with Zuckerman's sensation-seeking scale and genotyped for the Val158Met polymorphism (dbSNP:rs4680). Univariate analysis of variance showed that the sensation seeking score was significantly affected by a COMT genotype x gender interaction (F=5.330, df=2, p=0.005). The Val158Met polymorphism was associated with the sensation seeking personality trait in women only. The highest scores in the sensation-seeking scale and in three of the four subscales were observed in female subjects with the Val/Val genotype relative to women carrying the Met allele. Our results suggest that high COMT enzyme activity associated with the Val allele predisposes to high sensation seeking scores in female subjects and add to increasing evidence for a gender specific role of COMT in normal and dysfunctional behavior.

Charles Bonnet Syndrome: successful treatment of visual hallucinations due to vision loss with selective serotonin reuptake inhibitors.

Visual hallucinations are a common and often distressing consequence of vision loss, particularly in age-related macular degeneration. Charles Bonnet Syndrome (CBS) is defined by the triad of complex visual hallucinations, ocular pathology causing visual deterioration and preserved cognitive status. So far, although this condition is frequent, no established treatment for CBS has been stated. We report here the case of a 78-year-old woman, who came in our hospital because of a 4-week long mild depressive symptomatology. For 1 year she experienced daily sudden, unexpected, vivid and elaborate hallucinations. Insight was completely present, so the patient stated that the hallucinations were unreal and that the faces, geometrical figures and animals she saw every day were possibly due to her vision loss. The Mini Mental State Examination, digit span and verbal fluency were administered and no cognitive impairment was reported. The visual acuity was hand motion. After 4 days of treatment with venlafaxine the hallucinations completely disappeared. This is the first case to show that selective serotonin (and noradrenalin) reuptake inhibitors may be an effective and well-tolerated treatment for visual hallucinations associated with vision loss, and it adds to evidence implicating serotonergic pathways in the pathogenesis of visual hallucinations.