A. Mucci

Oxytocin receptor polymorphisms and adult attachment style in patients with depression

Much evidence of an association between specific attachment styles and depression prompted us to investigate, in depressive disorders, the potential role of polymorphisms within the gene encoding the receptor of the main neurohormone involved in attachment processes, oxytocin. For this purpose, two single nucleotide polymorphisms (SNPs), 6930G>A (rs53576) and 9073G>A (rs2254298), within the oxytocin receptor gene (OXTR), were studied in a cohort of 185 patients with major depression (50.3%) or bipolar I or II disorders (49.7%) and 192 matched healthy controls. A positive association between the GG genotype of OXTR SNPs (6930G>A or 9073G>A) and unipolar depression was demonstrated. In this group, GG individuals showed high scores on Attachment Style Questionnaire factors that have been previously associated with depression. Moreover, the GG genotype was also associated with high levels of adult separation anxiety. These findings support the involvement of the oxytocinergic system in the mechanisms that underlie depression and specific adult attachment styles.

The cortical generators of P3a and P3b: a LORETA study.

The P3 is probably the most well known component of the brain event-related potentials (ERPs). Using a three-tone oddball paradigm two different components can be identified: the P3b elicited by rare target stimuli and the P3a elicited by the presentation of rare non-target stimuli. Although the two components may partially overlap in time and space, they have a different scalp topography suggesting different neural generators. The present study is aimed at defining the scalp topography of the two P3 components by means of reference-independent methods and identifying their electrical cortical generators by using the low-resolution electromagnetic tomography (LORETA). ERPs were recorded during a three-tone oddball task in 32 healthy, right-handed university students. The scalp topography of the P3 components was assessed by means of the brain electrical microstates technique and their cortical sources were evaluated by LORETA. P3a and P3b showed different scalp topography and cortical sources. The P3a electrical field had a more anterior distribution as compared to the P3b and its generators were localized in cingulate, frontal and right parietal areas. P3b sources included bilateral frontal, parietal, limbic, cingulate and temporo-occipital regions. Differences in scalp topography and cortical sources suggest that the two components reflect different neural processes. Our findings on cortical generators are in line with the hypothesis that P3a reflects the automatic allocation of attention, while P3b is related to the effortful processing of task-relevant events.

Sources of Cortical Rhythms in Adults During Physiological Aging: A Multicentric EEG Study

This electroencephalographic (EEG) study tested whether cortical EEG rhythms (especially delta and alpha) show a progressive increasing or decreasing trend across physiological aging. To this aim, we analyzed the type of correlation (linear and nonlinear) between cortical EEG rhythms and age. Resting eyes‐closed EEG data were recorded in 108 young (Nyoung; age range: 18–50 years, mean age 27.3 ± 7.3 SD) and 107 elderly (Nold; age range: 51–85 years, mean age 67.3 ± 9.2 SD) subjects. The EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by low‐resolution brain electromagnetic tomography (LORETA). Statistical results showed that delta sources in the occipital area had significantly less magnitude in Nold compared to Nyoung subjects. Similarly, alpha 1 and alpha 2 sources in the parietal, occipital, temporal, and limbic areas had significantly less magnitude in Nold compared to Nyoung subjects. These nine EEG sources were given as input for evaluating the type (linear, exponential, logarithmic, and power) of correlation with age. When subjects were considered as a single group there was a significant linear correlation of age with the magnitude of delta sources in the occipital area and of alpha 1 sources in occipital and limbic areas. The same was true for alpha 2 sources in the parietal, occipital, temporal, and limbic areas. In general, the EEG sources showing significant linear correlation with age also supported a nonlinear correlation with age. These results suggest that the occipital delta and posterior cortical alpha rhythms decrease in magnitude during physiological aging with both linear and nonlinear trends. In conclusion, this new methodological approach holds promise for the prediction of dementia in mild cognitive impairment by regional source rather than surface EEG data and by both linear and nonlinear predictors. Hum Brain Mapp, 2005.

The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia.

In people suffering from schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Enhanced understanding of factors that hinder real‐life functioning is vital for treatments to translate into more positive outcomes. The goal of the present study was to identify predictors of real‐life functioning in people with schizophrenia, and to assess their relative contribution. Based on previous literature and clinical experience, several factors were selected and grouped into three categories: illness‐related variables, personal resources and context‐related factors. Some of these variables were never investigated before in relationship with real‐life functioning. In 921 patients with schizophrenia living in the community, we found that variables relevant to the disease, personal resources and social context explain 53.8% of real‐life functioning variance in a structural equation model. Neurocognition exhibited the strongest, though indirect, association with real‐life functioning. Positive symptoms and disorganization, as well as avolition, proved to have significant direct and indirect effects, while depression had no significant association and poor emotional expression was only indirectly and weakly related to real‐life functioning. Availability of a disability pension and access to social and family incentives also showed a significant direct association with functioning. Social cognition, functional capacity, resilience, internalized stigma and engagement with mental health services served as mediators. The observed complex associations among investigated predictors, mediators and real‐life functioning strongly suggest that integrated and personalized programs should be provided as standard treatment to people with schizophrenia.

Correlates of cognitive impairment in first episode schizophrenia: the EUFEST study.

BACKGROUND Profile and correlates of cognitive deficits in first episode (FE) schizophrenia patients are still debated. The present study is aimed to clarify in a large sample of FE patients the extent of impairment in key cognitive domains and its relationships with demographic and clinical variables. METHOD The European First Episode Schizophrenia Trial collected demographic, clinical and neurocognitive baseline data in 498 FE patients with minimal or no prior exposure to antipsychotics. Two-hundred-twenty healthy subjects (HS) were also evaluated. Neurocognitive assessment included the Rey Auditory Verbal Learning Test; Trail Making A and B, Purdue Pegboard and Digit-Symbol Coding. RESULTS Patients performed worse than HS on all tests (effect sizes from -0.88 to -1.73). Correlations with psychopathological dimensions were weak and involved reality distortion and disorganization. The duration of untreated psychosis (DUP) was not associated with cognitive impairment. Subjects living alone had a better neurocognitive performance, while the occupation status did not reveal any association with cognition. CONCLUSIONS A moderate/severe impairment of processing speed, motor dexterity, verbal memory and cognitive flexibility was found in the largest sample of FE patients analyzed so far. The impairment was largely independent from psychopathology and not associated with DUP.

Inhibition of auditory cortical responses to ipsilateral stimuli during dichotic listening: evidence from magnetoencephalography

The present magnetoencephalography (MEG) study on auditory evoked magnetic fields (AEFs) was aimed at verifying whether during dichotic listening the contralateral auditory pathway inhibits the ipsilateral one, as suggested by behavioural and patient studies. Ten healthy subjects were given a randomized series of three complex tones (261, 293 and 391 Hz, 500 ms duration), which were delivered monotically and dichotically with different intensities [60, 70 or 80 dBA (audio decibels)]. MEG data were recorded from the right auditory cortex. Results showed that the M100 amplitude over the right auditory cortex increased progressively when tones of increasing intensity were provided at the ipsilateral (right) ear. This effect on M100 was abolished when a concurrent tone of constant intensity was delivered dichotically at the contralateral (left) ear, suggesting that the contralateral pathway inhibited the ipsilateral one. The ipsilateral inhibition was present only when the contralateral tone fundamental frequency was similar to the ipsilateral tone. It was proposed that the occlusion mechanism would be exerted in cortical auditory areas as the dichotic effects were observed at M100 but not M50 component. This is the first evidence showing a neurophysiological inhibition driven by the contralateral auditory pathway over the ipsilateral one during dichotic listening.

Evidence-based medicine and electrophysiology in schizophrenia.

In research on schizophrenia electrophysiological measures have been investigated to identify biomarkers of the disorder, indices enabling differential diagnosis among psychotic disorders, prognostic indicators or endophenotypes. The present systematic review will focus on the most largely studied electrophysiological indices, i.e., qualitative or quantitative (limited to spectral analysis) EEG and the P300 event-related potential. The PubMed clinical query was used with research methodology filters for each of the following categories: diagnosis/prognosis/aetiology and a broad sensitive search strategy. The key-words: SCHIZOPHRENIA AND EEG/P3/P300 were used. The search results were then narrowed by including the terms “human” and “English language”, and cross-referenced. Systematic reviews and meta-analyses, when available, were also used for cross-referencing. Case reports and studies irrelevant to the topics and methodologies under examination were excluded. The remaining papers were screened to verify the eligibility for this systematic review. Inclusion criteria were: a) a diagnosis of schizophrenia confirmed by DSM-III/ICD-9 criteria (or later editions of the same classification systems); b) the inclusion of both a schizophrenia study group and an healthy control group (when appropriate, i.e., for P300 and quantitative EEG); c) qualitative or spectral EEG findings and amplitude measures for P300. The included studies were then reviewed to verify homogeneity of the results, as well as the presence of the information needed for the present systematic review and meta-analysis. Previous reviews and studies meeting the above requirements (n=22 for qualitative EEG; n=45 for spectral EEG and n=132 for P300) were classified according to the Oxford Centre for Evidence-based Medicine (EBM) levels of evidence criteria. For qualitative EEG as a diagnostic test, the majority of studies predated the introduction of DSM-III and were excluded from the review. Few post DSM-III studies investigated the usefulness of qualitative EEG in the differential diagnosis between schizophrenia and psychosis due to general medical condition. None of them was Oxford CEBM level 3b (non-consecutive-study or cohort-study without consistently-applied reference standard) or better (exploratory or validating cohort-study). No meta-analysis could be conducted due to the lack of reliable quantification methods in the reviewed studies. For spectral EEG as a diagnostic test, most studies qualified as level 4 (case-control study with poor reference standard), and only 24% as level 3b or better. An increase of slow activity in patients is reported by most of these studies. As to meta-analyses examining 29 studies, with 32 independent samples for the delta band and 35 for the theta band, a moderate effect size was found and only 1 study yielded findings in the opposite direction for both measures. There was no identified source for the discrepancy. The analysis of moderator factors included medication, band frequency limits, spectral parameters and disease stage. The medication status was significant for the theta band but the effect was unclear as findings for drug-naïve and drug-free patients were in a different direction. Chronicity had a significant effect on both delta and theta bands, with slow activity increase larger in chronic than in first episode patients. For P3 amplitude reduction as a diagnostic index, 63% of the studies qualified as level 3b or better. Meta-analysis (52 studies, 60 independent samples) results demonstrated a large effect size. None of the studies reported opposite findings. The analysis of moderator factors, including medication status and disease stage, revealed no significant effect on data heterogeneity. In conclusion, the examined indices are good candidates but are not ready yet for clinical applications aimed to improve present diagnostic standards for schizophrenia. Further research carried out according to adequate methodological standards and based on large scale multi-center studies is mandatory.

Persistent negative symptoms in first episode patients with schizophrenia: Results from the European First Episode Schizophrenia Trial

Negative symptoms that do not improve following antipsychotic treatment represent a challenge for development of effective treatments. Few studies have been carried out so far, especially in first-episode schizophrenia patients, to clarify prevalence, correlates and impact of persistent negative symptoms (PNS) on short- and long-term outcome of the disease. All patients from EUFEST study for whom both baseline and 12-month assessments were available were included (N=345). PNS were defined as the presence of at least one negative symptom of moderate or higher severity, not confounded by depression or parkinsonism, at baseline and after 1 year of treatment. Patients with PNS were compared to those with at least one negative symptom of moderate or higher severity at the baseline, not persisting after 1 year, on demographic, clinical, neurocognitive, global functioning and quality of life measures. PNS not confounded by depression or parkinsonism were present in 6.7% of the sample. The symptom that more often persisted was blunted affect. Patients with PNS differed from those without PNS for a longer duration of untreated psychosis (DUP) and a more frequent discontinuation of study treatment; they also had a poorer psychopathological outcome and a worse global functioning after 1 year of treatment. The presence of PNS was associated to poorer improvement of all psychopathological dimensions and worse global functioning after 1 year of treatment. The longer DUP in subjects with PNS suggests that programs aimed at shortening DUP might reduce the prevalence of PNS and improve prognosis of schizophrenia.

CEEG mapping in drug-free schizophrenics : differences from healthy subjects and changes induced by haloperidol treatment

A topographic CEEG investigation was carried out in 20 drug-free, DSM-IIIR diagnosed schizophrenics and in a group of matched healthy controls. The effects of acute and chronic haloperidol treatment were then assessed in the patient group. On the baseline recording, schizophrenics showed a widespread increase in delta, theta 1 and beta 3 amplitude. Acute haloperidol administration produced a decrease in delta and an increase in slow beta amplitude. After 28 days of treatment, delta and fast beta were reduced while theta 2 and alpha 1 were increased. CEEG abnormalities in schizophrenic subjects appear, therefore, to be reduced by chronic neuroleptic treatment.

Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback

Background The neurobiological underpinnings of avolition in schizophrenia remain unclear. Most brain imaging research has focused on reward prediction deficit and on ventral striatum dysfunction, but findings are not consistent. In the light of accumulating evidence that both ventral striatum and dorsal caudate play a key role in motivation, we investigated ventral striatum and dorsal caudate activation during processing of reward or loss in patients with schizophrenia. Method We used functional magnetic resonance imaging to study brain activation during a Monetary Incentive Delay task in patients with schizophrenia, treated with second-generation antipsychotics only, and in healthy controls (HC). We also assessed the relationships of ventral striatum and dorsal caudate activation with measures of hedonic experience and motivation. Results The whole patient group had lower motivation but comparable hedonic experience and striatal activation than HC. Patients with high avolition scores showed lower dorsal caudate activation than both HC and patients with low avolition scores. A lower dorsal caudate activation was also observed in patients with deficit schizophrenia compared to HC and patients with non-deficit schizophrenia. Dorsal caudate activity during reward anticipation was significantly associated with avolition, but not with anhedonia in the patient group. Conclusions These findings suggest that avolition in schizophrenia is linked to dorsal caudate hypoactivation.