The genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

Four reasons why early detection centers for psychosis should be renamed and their treatment targets reconsidered: we should not catastrophize a future we can neither reliably predict nor change.

Since the 1990s, facilities for individuals at putative risk for psychosis have mushroomed and within a very short time have become part of the standard psychiatric infrastructure in many countries. The idea of preventing a severe mental disorder before its exacerbation is laudable, and early data indeed strongly suggested that the sooner the intervention, the better the outcome. In this paper, the authors provide four reasons why they think that early detection or prodromal facilities should be renamed and their treatment targets reconsidered. First, the association between the duration of untreated psychosis and outcome is empirically established but has become increasingly weak over the years. Moreover, its applicability to those who are considered at risk remains elusive. Second, instruments designed to identify future psychosis are prone to many biases that are not yet sufficiently controlled. None of these instruments allows an even remotely precise prognosis. Third, the rate of transition to psychosis in at-risk patients is likely lower than initially thought, and evidence for the success of early intervention in preventing future psychosis is promising but still equivocal. Perhaps most importantly, the treatment is not hope-oriented. Patients are more or less told that schizophrenia is looming over them, which may stigmatize individuals who will never, in fact, develop psychosis. In addition self-stigma has been associated with suicidality and depression. The authors recommend that treatment of help-seeking individuals with mental problems but no established diagnosis should be need-based, and the risk of psychosis should be de-emphasized as it is only one of many possible outcomes, including full remission. Prodromal clinics should not be abolished but should be renamed and restructured. Such clinics exist, but the transformation process needs to be facilitated.

Risk profiles for heavy drinking in adolescence: differential effects of gender.

Abnormalities across different domains of neuropsychological functioning may constitute a risk factor for heavy drinking during adolescence and for developing alcohol use disorders later in life. However, the exact nature of such multi-domain risk profiles is unclear, and it is further unclear whether these risk profiles differ between genders. We combined longitudinal and cross-sectional analyses on the large IMAGEN sample (N ≈ 1000) to predict heavy drinking at age 19 from gray matter volume as well as from psychosocial data at age 14 and 19-for males and females separately. Heavy drinking was associated with reduced gray matter volume in 19-year-olds' bilateral ACC, MPFC, thalamus, middle, medial and superior OFC as well as left amygdala and anterior insula and right inferior OFC. Notably, this lower gray matter volume associated with heavy drinking was stronger in females than in males. In both genders, we observed that impulsivity and facets of novelty seeking at the age of 14 and 19, as well as hopelessness at the age of 14, are risk factors for heavy drinking at the age of 19. Stressful life events with internal (but not external) locus of control were associated with heavy drinking only at age 19. Personality and stress assessment in adolescents may help to better target counseling and prevention programs. This might reduce heavy drinking in adolescents and hence reduce the risk of early brain atrophy, especially in females. In turn, this could additionally reduce the risk of developing alcohol use disorders later in adulthood.

Evidence-based Treatment Options in Cannabis Dependency.

BACKGROUND: Now that the consumption of natural and synthetic cannabinoids is becoming more widespread, the specific treatment of cannabis-related disturbances is an increasingly important matter. There are many therapeutic options, and it is not always clear which ones are evidence-based and appropriate for use in a given clinical situation. METHODS: This review is based on reports of pertinent randomized and controlled trials (RCTs) that were retrieved by a selective search in the PubMed and Cochrane databases. RESULTS: Cognitive behavior therapy (CBT) combined with other techniques has been found to have a moderate to large effect (Cohen's d = 0.53-0.9) on the amount of cannabis consumed as well as on the level of psychosocial functioning or the dependence syndrome. Systemic multidimensional family therapy (MDFT) has been found beneficial for younger adolescents who consume large amounts of cannabis and have psychiatric comorbidities. Short-term interventions with motivational talk therapy have been found effective for patients with or without an initial desire to achieve cannabis abstinence. All of these psychotherapeutic interventions are effective at evidence level Ia. The administration of gabapentin had a weak effect (d = 0.26) on the quantity consumed and on abstinence (evidence level Ib). Withdrawal symptoms can be alleviated with cannabinoid-receptor antagonists (d = 0.223 and 0.481) (evidence level Ib). On the other hand, there is evidence that serotonergic antidepressants can worsen withdrawal manifestations and increase the likelihood of relapse. CONCLUSION: Psychotherapeutic techniques remain the foundation of treatment for cannabis dependence. No drug has yet been approved for the treatment of cannabis dependence because of the lack of scientific evidence. The rates of abstinence that are currently achieved, even with psychotherapy, are still only moderate. Further clinical studies are needed for the evaluation of combinations of various treatments that can meet the needs of individual patients.

Prefrontal and Striatal Glutamate Differently Relate to Striatal Dopamine: Potential Regulatory Mechanisms of Striatal Presynaptic Dopamine Function?

Theoretical and animal work has proposed that prefrontal cortex (PFC) glutamate inhibits dopaminergic inputs to the ventral striatum (VS) indirectly, whereas direct VS glutamatergic afferents have been suggested to enhance dopaminergic inputs to the VS. In the present study, we aimed to investigate relationships of glutamate and dopamine measures in prefrontostriatal circuitries of healthy humans. We hypothesized that PFC and VS glutamate, as well as their balance, are differently associated with VS dopamine. Glutamate concentrations in the left lateral PFC and left striatum were assessed using 3-Tesla proton magnetic resonance spectroscopy. Striatal presynaptic dopamine synthesis capacity was measured by fluorine-18-l-dihydroxyphenylalanine (F-18-FDOPA) positron emission tomography. First, a negative relationship was observed between glutamate concentrations in lateral PFC and VS dopamine synthesis capacity (n = 28). Second, a positive relationship was revealed between striatal glutamate and VS dopamine synthesis capacity (n = 26). Additionally, the intraindividual difference between PFC and striatal glutamate concentrations correlated negatively with VS dopamine synthesis capacity (n = 24). The present results indicate an involvement of a balance in PFC and striatal glutamate in the regulation of VS dopamine synthesis capacity. This notion points toward a potential mechanism how VS presynaptic dopamine levels are kept in a fine-tuned range. A disruption of this mechanism may account for alterations in striatal dopamine turnover as observed in mental diseases (e.g., in schizophrenia). SIGNIFICANCE STATEMENT: The present work demonstrates complementary relationships between prefrontal and striatal glutamate and ventral striatal presynaptic dopamine using human imaging measures: a negative correlation between prefrontal glutamate and presynaptic dopamine and a positive relationship between striatal glutamate and presynaptic dopamine are revealed. The results may reflect a regulatory role of prefrontal and striatal glutamate for ventral striatal presynaptic dopamine levels. Such glutamate-dopamine relationships improve our understanding of neurochemical interactions in prefrontostriatal circuits and have implications for the neurobiology of mental disease.

Frontal glutamate and reward processing in adolescence and adulthood.

The fronto-limbic network interaction, driven by glutamatergic and dopaminergic neurotransmission, represents a core mechanism of motivated behavior and personality traits. Reward seeking behavior undergoes tremendous changes in adolescence paralleled by neurobiological changes of this network including the prefrontal cortex, striatum and amygdala. Since fronto-limbic dysfunctions also underlie major psychiatric diseases beginning in adolescence, this investigation focuses on network characteristics separating adolescents from adults. To investigate differences in network interactions, the brain reward system activity (slot machine task) together with frontal glutamate concentration (anterior cingulate cortex, ACC) was measured in 28 adolescents and 26 adults employing functional magnetic resonance imaging and magnetic resonance spectroscopy, respectively. An inverse coupling of glutamate concentrations in the ACC and activation of the ventral striatum was observed in adolescents. Further, amygdala response in adolescents was negatively correlated with the personality trait impulsivity. For adults, no significant associations of network components or correlations with impulsivity were found. The inverse association between frontal glutamate concentration and striatal activation in adolescents is in line with the triadic model of motivated behavior stressing the important role of frontal top-down inhibition on limbic structures. Our data identified glutamate as the mediating neurotransmitter of this inhibitory process and demonstrates the relevance of glutamate on the reward system and related behavioral traits like impulsivity. This fronto-limbic coupling may represent a vulnerability factor for psychiatric disorders starting in adolescence but not in adulthood.

Neural correlates of alcohol-approach bias in alcohol addiction: the spirit is willing but the flesh is weak for spirits.

Behavioral studies have shown an alcohol-approach bias in alcohol-dependent patients: the automatic tendency to faster approach than avoid alcohol compared with neutral cues, which has been associated with craving and relapse. Although this is a well-studied psychological phenomenon, little is known about the brain processes underlying automatic action tendencies in addiction. We examined 20 alcohol-dependent patients and 17 healthy controls with functional magnetic resonance imaging (fMRI), while performing an implicit approach-avoidance task. Participants pushed and pulled pictorial cues of alcohol and soft-drink beverages, according to a content-irrelevant feature of the cue (landscape/portrait). The critical fMRI contrast regarding the alcohol-approach bias was defined as (approach alcohol>avoid alcohol)>(approach soft drink>avoid soft drink). This was reversed for the avoid-alcohol contrast: (avoid alcohol>approach alcohol)>(avoid soft drink>approach soft drink). In comparison with healthy controls, alcohol-dependent patients had stronger behavioral approach tendencies for alcohol cues than for soft-drink cues. In the approach, alcohol fMRI contrast patients showed larger blood-oxygen-level-dependent responses in the nucleus accumbens and medial prefrontal cortex, regions involved in reward and motivational processing. In alcohol-dependent patients, alcohol-craving scores were positively correlated with activity in the amygdala for the approach-alcohol contrast. The dorsolateral prefrontal cortex was not activated in the avoid-alcohol contrast in patients vs controls. Our data suggest that brain regions that have a key role in reward and motivation are associated with the automatic alcohol-approach bias in alcohol-dependent patients.

Animal-assisted therapy and agitation and depression in nursing home residents with dementia: a matched case-control trial.

OBJECTIVES: To investigate the efficacy of animal-assisted therapy (AAT) on symptoms of agitation/aggression and depression in nursing home residents with dementia in a randomized controlled trial. Previous studies have indicated that AAT has beneficial effects on neuropsychiatric symptoms in various psychiatric disorders but few studies have investigated the efficacy of AAT in patients suffering from dementia. METHODS: Of 65 nursing home residents with dementia (mean [standard deviation] age: 81.8 [9.2] years; mean Mini-Mental State Examination score: 7.1 [0.7]), 27 matched pairs (N = 54) were randomly assigned to either treatment as usual or treatment as usual combined with AAT, administered over 10 weekly sessions. Blinded raters assessed cognitive impairment with the Mini-Mental State Examination, presence of agitation/aggression with the Cohen-Mansfield Agitation Inventory, and depression with the Dementia Mood Assessment Scale at baseline and during a period of 4 weeks after AAT intervention. RESULTS: In the control group, symptoms of agitation/aggression and depression significantly increased over 10 weeks; in the intervention group, patients receiving combined treatment displayed constant frequency and severity of symptoms of agitation/aggression (F1,48 = 6.43; p <0.05) and depression (F1,48 = 26.54; p <0.001). Symptom amelioration did not occur in either group. CONCLUSIONS: AAT is a promising option for the treatment of agitation/aggression and depression in patients with dementia. Our results suggest that AAT may delay progression of neuropsychiatric symptoms in demented nursing home residents. Further research is needed to determine its long-time effects.

Variables involved in the cue modulation of the startle reflex in alcohol-dependent patients.

Cue modulation of the startle reflex is a paradigm that has been used to understand the emotional mechanisms involved in alcohol dependence. Attenuation of the startle reflex has been demonstrated when alcohol-dependent subjects are exposed to alcohol-related stimuli. However, the role of clinical variables on the magnitude of this response is unknown. The objective of this study was to determine the relationship between a number of clinical variables-severity of alcoholism, family history of alcoholism (FHA+), personality traits related to the sensitivity to reward-and the startle reflex response when subjects with alcohol dependence were viewing alcohol-related cues. After detoxification, 98 participants completed self-report instruments and had eye blink electromyograms measured to acoustic startle probes [100-millisecond burst of white noise at 95 dB(A)] while viewing alcohol-related pictures, and standardised appetitive, aversive and neutral control scenes. Ninety-eight healthy controls were also assessed with the same instruments. There were significant differences on alcohol-startle magnitude between patients and controls. Comparisons by gender showed that women perceived alcohol cues and appetitive cues more appetitive than men. Male and female patients showed more appetitive responses to alcohol cues when compared with their respective controls. Our patients showed an appetitive effect of alcohol cues that was positively related to severity of alcohol dependence, sensitivity to reward and a FHA+. The data confirmed that the pattern of the modulation of the acoustic startle reflex reveals appetitive effects of the alcohol cues and extended it to a variety of clinical variables.

A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms?

Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N = 54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level-dependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward-related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group.

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.

Central serotonin transporter levels are associated with stress hormone response and anxiety.

RATIONALE: Negative mood states are characterized by both stress hormone dysregulation and serotonergic dysfunction, reflected by altered thalamic serotonin transporter (5-HTT) levels. However, so far, no study examined the individual association between cortisol response and cerebral in vivo 5-HTT levels in patients suffering from negative mood states. OBJECTIVE: The objective of this cross-sectional study was to assess the interrelation of cortisol response, thalamic 5-HTT levels, and anxiety in healthy subjects and two previously published samples of patients with unipolar major depression (UMD) and obsessive-compulsive disorder (OCD), controlling for age, gender, 5-HTT genotype, smoking, and seasonality. METHODS: Regional 5-HTT levels and cortisol response to dexamethasone-corticotropin (Dex-CRH) challenge were assessed in consecutive samples of medication-free patients suffering from UMD (N = 10) and OCD (N = 10), and 20 healthy volunteers. The intervention used was combined Dex-CRH test and [(11)C]DASB positron emission tomography. The main outcome measures were: 5-HTT binding potential (BP(ND)) in a predefined thalamic ROI, cortisol response defined as the maximum cortisol increase in the combined Dex-CRH-test, and state of anxiety from the state-trait-anxiety inventory. RESULTS: Reduced thalamic 5-HTT BP(ND) was associated with increased cortisol response (r = -0.35, p < 0.05; in patients: r = -0.53, p < 0.01) and with increased state anxiety (r = -0.46, p < 0.01), surviving correction for age, gender, 5-HTT genotype, smoking, and seasonality (p < 0.05). The 5-HTT genotype, on the contrary, was not significantly associated with cortisol response (p = 0.19) or negative mood (p = 0.23). CONCLUSION: The association between stress hormone response, thalamic 5-HTT levels, and anxiety in patients suffering from negative mood states suggests an interaction between two major mechanisms implicated in negative mood states in humans.

Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons.

Lithium salts are mood-stabilizing agents with acute antimanic properties and proven efficacy in the long-term prevention of manic and depressive episodes. Furthermore, lithium augmentation is a well-established strategy to treat depressed patients, which do not respond to antidepressants alone. There is evidence to suggest that these effects of lithium are due to a synergism with central serotonin (5-HT) neurotransmission. In this study, we investigated the effects of lithium chloride (LiCl, 1 mM) on 5-HT uptake and release in primary serotonergic neurons from rat raphe nuclei. Short-term (8 h) and long-term (14 days) treatment with LiCl resulted in a 20% and 23% increase in 5-HT release, but neither influenced 5-HT uptake across the plasma membrane nor vesicular 5-HT uptake. In lithium-treated raphe neurons, the inhibition of 5-HT uptake by fluoxetine was unchanged. Using real-time reverse transcriptase polymerase chain reaction and Western blotting, we examined the effect of lithium on tryptophan hydroxylase 2 (TPH2) expression, the rate-limiting enzyme in brain 5-HT biosynthesis. Short-term lithium treatment resulted in a 45% decrease in tph2 mRNA expression and a 31% reduction of TPH2 protein levels, which was completely compensated after long-term treatment. Our results suggest that lithium can modify tph2 gene expression and 5-HT release in raphe neurons, providing new insight into the serotonergic mechanisms of action of lithium.

High-frequency stimulation of the nucleus accumbens core and shell reduces quinpirole-induced compulsive checking in rats.

Electrical deep brain stimulation (DBS) is currently studied in the treatment of therapy-refractory obsessive compulsive disorders (OCDs). The variety of targeted brain areas and the inconsistency in demonstrating anti-compulsive effects, however, highlight the need for better mapping of brain regions in which stimulation may produce beneficial effects in OCD. Such a goal may be advanced by the assessment of DBS in appropriate animal models of OCD. Currently available data on DBS of the nucleus accumbens (NAc) on OCD-like behavior in rat models of OCD are contradictory and partly in contrast to clinical data and theoretical hypotheses about how the NAc might be pathophysiologically involved in the manifestation of OCD. Consequently, the present study investigates the effects of DBS of the NAc core and shell in a quinpirole rat model of OCD. The study demonstrates that electrical modulation of NAc core and shell activity via DBS reduces quinpirole-induced compulsive checking behavior in rats. We therefore conclude that both, the NAc core and shell constitute potential target structures in the treatment of OCD.

Serotonergic dysfunction in the prodromal, first-episode and chronic course of schizophrenia as assessed by the loudness dependence of auditory evoked activity.

Recent studies revealing evidence of increased serotonergic neurotransmission in schizophrenia has generated substantial interest in the role of serotonin in its pathophysiology. None of these studies, however, have queried whether dysfunctional serotonergic activity might already have been present in subjects of at-risk mental state for schizophrenia before the onset of psychotic symptoms, and whether serotonergic activity further increases during the development of schizophrenia and the chronic course. Although no valid indicator for measuring the activity level of serotonergic neurotransmission has yet been found, a series of evidence from human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. We examined the LDAEP (N1/P2 component) in 60 patients with at-risk mental state for schizophrenia who showed characteristic prodromal symptoms, 34 first-episode patients, 28 patients with a chronic course of schizophrenia and 57 healthy controls. Prodromal patients showed significantly weaker LDAEP in comparison to healthy volunteers, but similarly to that in first-episode and chronic patients. None of the covariates such as age, gender, medication, age of onset, or psychopathology had an influence on this finding. In a subsample of prodromal patients, LDAEP values remain the same after retesting 10 months later. These results indicate that serotonergic neurotransmission had already increased before the onset of the full-blown psychosis of schizophrenia and remains enhanced in the further course of the disease. A weak LDAEP may therefore represent a vulnerability marker rather than an expression of illness progression.

Cultural factors in the diagnosis and treatment of traumatised migrant patients from Turkey.

The process of migration may be associated not only with great hope, but also with distressing experiences that can lead to trauma and posttraumatic stress disorders. Although some of the symptoms induced by trauma are common across cultures, the strategies used to deal with them are often culture-specific. In the following paper, we consider the unique aspects of trauma-focused psychotherapy in patients with a history of migration. We discuss a variety of culture-specific factors with the help of two case histories.

Reduction of auditory event-related P300 amplitude in subjects with at-risk mental state for schizophrenia.

Neurophysiological methods allow the examination of cognitive-cortical functioning in patients with schizophrenia in its prodromal states. As revealed by previous studies, event-related potential components such as auditory evoked P300 associated with cognitive processes, such as attention and orientation, are known to be reduced in amplitude in acute and chronic as well as in medicated and unmedicated patients. It is, however, unclear whether a P300 amplitude reduction occurs before the schizophrenic psychosis is fully manifested. We studied patients in the prodromal phase of the schizophrenic disorder (i.e. subjects with an at-risk mental state showing attenuated psychotic symptoms or brief limited intermittent symptoms) as well as first-episode patients and chronic patients with schizophrenia and compared these groups to healthy subjects. The event-related P300 was recorded during an auditory oddball paradigm. Groups differed significantly from each other in the P300 amplitude at Pz (F(3/149)=2.532, p=0.02). Post-hoc tests revealed significantly lower P300 amplitudes of non-medicated prodromal (p=.03), first-episode (p=.01) and chronic patients (p=.001) compared to the healthy controls. The study revealed that there are neurophysiological changes as the reduction in P300 amplitudes begins early in schizophrenia at the prodromal phase, i.e. before a manifestation of full-blown psychosis, and that these changes seem to have a progressive course from prodromal to chronic state of schizophrenia as assumed in this cross-sectional study.

Different neural systems adjust motor behavior in response to reward and punishment.

Individuals use the outcomes of their actions to adjust future behavior. However, it remains unclear whether the same neural circuits are used to adjust behavior due to rewarding and punishing outcomes. Here we used functional magnetic resonance imaging (fMRI) and a reward-providing reaction time task to investigate the adaptation of a simple motor response following four different outcomes (delivery versus omission and monetary gain versus loss). We found that activation in the thalamus and insula predicted adjustments of motor responses due to outcomes that were cued and delivered, whereas activation in the ventral striatum predicted such adjustments when outcomes were cued but omitted. Further, activation of OFC predicted improvement after all punishing outcomes, independent of whether they were omitted rewards or delivered punishments. Finally, we found that activity in anterior cingulate predicted adjustment after delivered punishments and activity in dorsal striatum predicted adaptation after delivered rewards. Our results provide evidence that different but somewhat overlapping circuits mediate the same behavioral adaptation when it is driven by different incentive outcomes.

Reduced fMRI activation of an occipital area in recently detoxified alcohol-dependent patients in a visual and acoustic stimulation paradigm.

Chronic alcohol consumption is associated with neural damage that manifests in deficits in information processing. Previous studies evaluated higher cognitive functions such as working memory, but basic sensory information processing circuits have never been investigated before. Therefore, we applied a simple visual and acoustic stimulation paradigm in this functional magnetic resonance imaging (fMRI) pilot study. Nine recently detoxified male alcohol-dependent patients and nine healthy volunteers were presented a well-established 6-Hz checkerboard and auditory stimuli in the form of drumbeats in a block-design fMRI paradigm. During visual and acoustic stimulation, alcoholics and controls activated widespread occipital and temporal brain areas, as well as parts of the dorsolateral prefrontal cortex and thalamus. In a comparison of the stimulation-induced activation of alcoholics and controls, the alcoholics showed a significantly lower blood oxygen level dependent (BOLD) signal in an extended bilateral occipital area (P < 0.001) as compared with healthy controls. In no region was the BOLD signal significantly higher in the alcohol-dependent subjects compared with controls. The reason for the new finding of a highly significant lower activation of the occipital cortex is unclear. It is in line with studies of neuropsychological tests in recently detoxified alcohol-dependent patients that also reported deficits in visual abilities. Attention deficits or a persisting neuronal alteration in the first weeks of alcohol abstinence may have contributed to this result.

Is the loudness dependence of auditory evoked potentials modulated by the selective serotonin reuptake inhibitor citalopram in healthy subjects?

The loudness dependence of auditory evoked potentials (LDAEP) has been discussed as a non-invasive in vivo marker of central serotonergic function. Evidence for this has been found in animal studies, but studies in humans provide less consistent results. In this study, the relationship between LDAEP and directly modulated central serotonergic activity in healthy subjects was investigated. In a single-blind cross-over design, the LDAEP of female participants (age: 24.0 +/- 2.3 years) was measured under two conditions: (1) infusion of 20 mg citalopram diluted in 250 ml 0.9% saline and (2) infusion of 250 ml 0.9% saline as placebo. LDAEP was measured at five different time points before, during and up to 60 min after drug/placebo administration and dipole source analysis was performed. The increase of the central serotonin activity in response to citalopram was not accompanied by a significant change of the LDAEP compared to the placebo condition. The result underlines that the acceptance of LDAEP as a marker of central serotonergic function still needs further discussion.