Umberto Volpe

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.

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.

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.

Stereotaxy-Based Regional Brain Volumetry Applied to Segmented MRI: Validation and Results in Deficit and Nondeficit Schizophrenia

A method for postprocessing of segmented routine brain MRI studies providing automated definition of major structures (frontal, parietal, occipital, and temporal lobes; cerebellar hemispheres; and lateral ventricles) according to the Talairach atlas is presented. The method was applied to MRI studies from 25 normal subjects (NV), 14 patients with deficit schizophrenia (DS), and 14 with nondeficit schizophrenia (NDS), to evaluate their gray matter and CSF regional volumes. The two patient groups did not differ in mean age at illness onset, duration of illness, severity of psychotic symptoms, or disorganization; DS had more severe avolition and worse social functioning than NDS. For validation purposes, brain structures were manually outlined on original MR images in 10 studies, thus obtaining reference measures. Manual and automated measures were repeated 1 month apart to measure reproducibilities of both methods. The automated method required less than 1 min/operator per study vs more than 30 min for manual assessment. Mean absolute difference per structure between the two techniques was 4.8 ml. Overall reproducibility did not significantly differ between the two methods. In subjects with schizophrenia, a significant decrease in GM and increase in CSF were found. GM loss was confined to frontal and temporal lobes. Lateral ventricles were significantly larger bilaterally in NDS compared to NV and only on the right in NDS compared to DS. The finding of greater structural brain abnormalities in NDS adds to the evidence that deficit schizophrenia does not represent just the more severe end of the schizophrenia continuum.

Double dissociation of N1 and P3 abnormalities in deficit and nondeficit schizophrenia

It has been proposed that the presence of enduring, idiopathic negative symptoms define a group of patients with a disease (deficit schizophrenia, DS) that is separate from other forms of schizophrenia (nondeficit schizophrenia, NDS). Although several findings support this hypothesis, the possibility that DS represents the severe end of a single schizophrenia continuum cannot be excluded yet. We tested the hypothesis that DS and NDS differ relative to event-related potentials (ERPs). Amplitude, scalp topography and cortical sources of the ERP components were assessed in clinically stable DS and NDS outpatients and in matched healthy subjects (HCS). Twenty subjects per group were recruited. Among the subjects who completed the target detection task, there were no group difference in accuracy. For N1, only patients with DS, as compared with HCS, showed an amplitude reduction over the scalp central leads and a reduced current source density in cingulate and parahippocampal gyrus. For P3, only patients with NDS, as compared with HCS, showed a lateralized amplitude reduction over the left posterior regions and reduced current source density in left temporal and bilateral frontal, cingulate and parietal areas. The DS and NDS groups differed significantly from each other with regard to N1 amplitude and topography, as well as P3 amplitude and cortical sources. The N1 was affected in DS but not in NDS patients, whereas P3 was affected in NDS only. This double dissociation is consistent with the hypothesis that DS represents a separate disease entity within schizophrenia.

Pharmaco-EEG in Psychiatry

In spite of its origins deeply rooted in the discipline, pharmaco-EEG applications in psychiatry remain limited to its achievements in the field of psychotropic drugs classification and, in few instances, discovery. In the present paper two attempts to transfer pharmaco-EEG methods to psychiatric clinical routine will be described: 1) monitoring of psychotropic drug toxicity at the central nervous system level, and 2) prediction of clinical response to treatment with psychotropic drugs. Both applications have been the object of several investigations providing promising and sometimes consistent findings which, however, had no impact on clinical practice. For the first topic, the review is limited to antipsychotics, lithium and recreational drugs, as for other psychotropic drugs mostly case studies are available, while for the response prediction it will include antipsychotics, antidepressants, anxiolytics, psychostimulants and nootropics. In spite of several methodological limitations, pharmaco-EEG studies dealing with monitoring of antipsychotic- and lithium-induced EEG abnormalities went close to, but never became, a clinical routine. EEG studies of recreational drugs are flawed by several limitations, and failed, so far, to identify reliable indices of CNS toxicity to be used in clinical settings. Several QEEG studies on early predictors of treatment response to first generation antipsychotics have produced consistent findings, but had no clinical impact. For other psychotropic drug classes few and inconsistent reports have appeared. Pharmaco-EEG had the potential for important clinical applications, but so far none of them entered clinical routine. The ability to upgrade theories and methods and promote large scale studies represent the future challenge.

Task demand modulations of visuospatial processing measured with functional magnetic resonance imaging

Brain imaging based on functional magnetic resonance imaging (fMRI) provides a useful tool to examine neural networks and cerebral structures subserving visuospatial function. It allows not only the qualitative determination of which areas are active during task processing, but also estimates the quantitative contribution of involved brain regions to different aspects of spatial processing. In this study, we investigated in 10 healthy subjects how the amount of task (computational) demand in an angle discrimination task was related to neural activity as measured with event-related fMRI. Task demand, indicated by behavioral performance, was modulated by presenting clocks with different angular disparity and length of hands. Significant activations were found in the cortical network subserving the visual and visuospatial processing, including the right and left superior parietal lobules (SPL), striate visual areas, and sensorimotor areas. Both blood oxygenation level-dependent (BOLD) signal strength and spatial extent of activation in right as well as left SPL increased with task demand. By contrast, no significant correlation or a very weak correlation was found between the task demand and the BOLD signal as well as between task demand and spatial extent of activations in the striate visual areas and in the sensorimotor areas. These results support the hypothesis that increased computational demand requires more brain resources. The brain regions that are most specialized for the execution of the visuospatial task can be assessed by relating the imposed task demand to the functional activation measured.

Executive hypercontrol in obsessive-compulsive disorder: electrophysiological and neuropsychological indices

OBJECTIVE Neuropsychological, brain imaging and electrophysiological research have consistently shown a dysfunction of fronto-striato-thalamic pathways in subjects with obsessive-compulsive disorder (OCD). The functional meaning of the observed dysfunction in the pathogenesis of OCD is still debated. In the present study the hypothesis that it might be related to a hyperactive executive control is explored by means of neuropsychological and electrophysiological measures. METHODS Multilead quantitative EEG (QEEG) characteristics and neuropsychological performance on tests exploring executive functions, attention, short-term memory and the ability to learn supraspan recurring sequences were investigated in 32 drug-free patients with DSM-IV OCD. Multilead QEEG characteristics were also investigated in 32 healthy controls, matched with patients for age, gender and handedness. RESULTS A decrease of the slow alpha-band power in OCD as compared to healthy subjects was observed. A significant negative correlation between the slow alpha-band power and the time to complete a neuropsychological test exploring executive functions was found: the more reduced the slow alpha-band power, the slower the performance on this test. CONCLUSIONS The topographic distribution of the observed QEEG abnormalities, as well as their correlations with neuropsychological indices, suggest an increased activation of frontal networks in OC patients. SIGNIFICANCE Study findings support the presence of a hyperactivity of attention/executive control mechanisms in obsessive-compulsive patients.

Induced Gamma Activity and Event-Related Coherence in Schizophrenia

Evidence has been provided that high frequency oscillations within the gamma band reflect mechanisms of cortical integration. In the light of recently proposed pathophysiological models of schizophrenia, suggesting a disturbance of the functional connectivity within distributed neural networks, it has been hypothesized that abnormalities in the gamma band underlie perceptual and cognitive dysfunctions in patients with schizophrenia. In the present study we investigated evoked and induced 40-Hz gamma power as well as frontoparietal and frontotem-poral event-related coherence in patients with deficit and nondeficit schizophrenia and in matched healthy controls. In patients, correlations between gamma oscillations and psychopathological dimensions were also investigated. A reduction of both induced gamma power and event-related coherence was observed in patients with nondeficit schizophrenia, but not in those with deficit schizophrenia. Our findings support the hypothesis that deficit and nondeficit schizophrenia represent separate disease entities, suggesting the presence of a poor integration of the neuronal activity within distributed neural network only in the subgroup of schizophrenic patients without primary and persistent negative symptoms. Associations between an excess of gamma oscillations and psychopathological dimensions were observed, suggesting that abnormal thoughts, behaviors and perceptions might be related to the formation of inappropriate neural connections.

Dorsolateral prefrontal cortex volume in patients with deficit or nondeficit schizophrenia

Deficit schizophrenia (DS) represents a promising putative clinical subtype of schizophrenia and is characterized by the presence of primary and enduring negative symptoms. Previous studies have often reported a reduced amount of gray matter within prefrontal and temporal cortices in schizophrenia subjects with prevailing negative symptoms; however, the evidence concerning brain structural abnormalities in patients with DS remains controversial. The aim of the present study was to investigate whether patients with DS differed from those with nondeficit schizophrenia (NDS) with respect to the volume of the dorsolateral prefrontal cortex (DLPFC) and hippocampus, two brain areas considered as key regions in the pathogenesis of schizophrenia. In the present study a 3D-T1w MR imaging procedure and an extensive clinical assessment was carried out in 18 patients with schizophrenia, (10 DS and 8 NDS). 3D MPRAGE images were preprocessed with SPM software and two regions of interest (hippocampus and DLPFC) were manually traced to obtain their gray matter volumes. We found a significant reduction of DLPFC in the entire schizophrenia group, with respect to healthy subjects. Although the subgroup of patients with DS had a more severe clinical picture and more impaired social functioning, the DLPFC volume reduction was greater in NDS than in DS patients. In conclusion, according to our structural neuroimaging findings, DS patients, although characterized by a more severe clinical picture and a worse outcome, show less neurobiological abnormalities.