Pietro Bria

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines.

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1β, TNF-α or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1β, TNF-α or even IL-18, in patients with poststroke depression.

Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation

Repetitive transcranial magnetic stimulation (rTMS) of human motor cortex can produce long-lasting changes in the excitability of excitatory and inhibitory neuronal networks. The effects of rTMS depend critically on stimulus frequency. The aim of our present study was to compare the effects of different rTMS protocols. We compared the aftereffects of 6 different rTMS protocols [paired associative stimulation at interstimulus intervals of 25 (PAS(25)) and 10 ms (PAS(10)); theta burst stimulation delivered as continuous (cTBS) or intermittent delivery pattern (iTBS); 1- and 5-Hz rTMS] on the excitability of stimulated and contralateral motor cortex in 10 healthy subjects. A pronounced increase of cortical excitability, evaluated by measuring the amplitude of motor evoked potentials (MEPs), was produced by iTBS (+56%) and PAS(25) (+45%). Five-hertz rTMS did not produce a significant increase of MEPs. A pronounced decrease of cortical excitability was produced by PAS(10) (-31%), cTBS (-29%), and 1-Hz rTMS (-20%). Short-interval intracortical inhibition was suppressed by PAS(10). Cortical silent period duration was increased by 1-Hz stimulation. No significant effect was observed in the contralateral hemisphere. Head-to-head comparison of the different protocols enabled us to identify the most effective paradigms for modulating the excitatory and inhibitory circuits activated by TMS.

GABAA receptor subtype specific enhancement of inhibition in human motor cortex.

Inhibition is of fundamental importance to regulate activity in cortical circuits. Inhibition is mediated through a diversity of different interneurones and γ‐aminobutyric acid A receptor (GABAAR) subtypes. Here we employed paired‐pulse transcranial magnetic stimulation (TMS) to measure short interval intracortical inhibition (SICI), a GABAAR‐mediated inhibition in human motor cortex, to address the question of which GABAAR subtype is responsible for this form of inhibition. It has been shown that classical benzodiazepines (diazepam and lorazepam) have a non‐selective affinity profile at different α‐subunit‐bearing subtypes of the GABAAR while zolpidem has a 10‐fold greater affinity to the α1‐subunit‐bearing GABAAR compared with those bearing the α2‐ or α3‐subunit. We found that, in seven healthy subjects, a single oral dose of 20 mg of diazepam or 2.5 mg of lorazepam significantly increased SICI, whereas 10 mg of zolpidem did not change SICI. This dissociation occurred despite equal sedation by all three drugs, an α1‐subunit GABAAR‐mediated effect. The findings strongly suggest that SICI is not mediated by the α1‐subunit‐bearing subtype of the GABAAR but by those bearing either the α2‐ or α3‐subunit. This study represents an attempt by means of TMS to identify GABAAR subtype‐specific action at the systems level of human cortex, a highly relevant issue because the different α‐subunit‐bearing subtypes of the GABAAR are differently involved in benzodiazepine‐mediated effects such as sedation, amnesia or anxiolysis, in developmental cortical plasticity, and in neurological disorders such as epilepsy.

Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: a TMS study.

OBJECTIVE To investigate if different interneuronal circuits in human motor cortex mediate inhibition through different subtypes of the gamma-aminobutyric acid A receptor (GABAAR). METHODS Two distinct forms of motor cortical inhibition were measured in 10 healthy subjects by established transcranial magnetic stimulation (TMS) protocols: short interval intracortical inhibition (SICI) and short latency afferent inhibition (SAI). Their modification by a single oral dose of three different positive GABAAR modulators (20 mg of diazepam, 2.5 mg of lorazepam and 10 mg of zolpidem) with different affinity profiles at the various alpha-subunit bearing subtypes of the GABAAR (diazepam: non-selective, lorazepam: unknown, zolpidem: 10-fold higher affinity to alpha1- than alpha2- or alpha3-subunit bearing GABAARs, no affinity to alpha5-subunits) was tested in a randomized crossover design. In addition, the sedative drug effects were recorded by a visual analogue scale. RESULTS Diazepam and lorazepam increased SICI, whereas zolpidem did not change SICI. In contrast, diazepam had no effect on SAI, whereas lorazepam and zolpidem decreased SAI. The sedative effects were not different between drugs. CONCLUSIONS The dissociating patterns of drug modification of SICI versus SAI strongly suggest that different GABAAR subtypes are involved in SICI and SAI. SIGNIFICANCE We provide evidence, for the first time, for a dissociation of effects of diazepam and zolpidem on SAI and confirm the previously reported differential effect of zolpidem and of diazepam and lorazepam on SICI. The differential effects of the three benzodiazepines on SAI and SICI suggest that neuronal circuits in human motor cortex that mediate inhibition through different GABAAR subtypes can be segregated by TMS.

Prefrontal–thalamic–cerebellar gray matter networks and executive functioning in schizophrenia

OBJECTIVE Poor executive functioning is a core deficit in schizophrenia and has been linked to frontal lobe alterations. We aimed to identify (1) prefrontal cerebral areas in which decreased volume is linked to executive dysfunction in schizophrenia; and (2) areas throughout the brain that are volumetrically related to the prefrontal area identified in the first analysis, thus detecting more extended volumetric networks associated with executive functioning. METHOD Fifty-three outpatients with schizophrenia and 62 healthy controls, matched for age, gender and handedness, were recruited. High-resolution images were acquired on a 1.5 tesla scanner and regional gray and white matter volumes were analyzed by voxel-based morphometry within SPM5 (statistical parametric mapping, University College London, UK). Executive functioning was assessed using the Wisconsin Card Sorting Test (WCST). RESULTS Twenty-one patients with poor executive functioning showed reduced dorsolateral prefrontal and anterior cingulate gray matter volume as compared to 30 patients with high WCST performance, with a maximum effect in the left dorsolateral prefrontal cortex. Left dorsolateral prefrontal gray matter volume predicted WCST performance after controlling for possible confounding effects of global cognitive functioning, verbal attention span, negative symptoms, illness duration and education. In this area, both patient groups had less gray matter than healthy controls. Left dorsolateral prefrontal gray matter volume was positively related to dorsal prefrontal, anterior cingulate and parietal gray matter volume; and negatively related to thalamic, cerebellar, pontine and right parahippocampal gray matter volume. CONCLUSIONS Volumetric alterations in prefrontal-thalamic-cerebellar gray matter networks may lead to executive dysfunction in schizophrenia.

Internet addiction: hours spent online, behaviors and psychological symptoms

OBJECTIVE The aim of this study was to investigate psychopathological symptoms, behaviors and hours spent online in patients with internet addiction disorder (IAD) at a new psychiatric service for IAD inside a policlinic. METHOD Eighty-six subjects participated in the study. Thirty-three patients asking for psychiatric consultation regarding their excessive use of the internet were assessed with IAD interview, internet addiction test (IAT), Symptom Checklist-90-Revised (SCL-90-R) and a brief sociodemographic survey. Moreover, patients had to respond to the following question: Over the last month, how much time have you spent online per week? At the end of psychiatric assessment, 21 of the 33 patients satisfied inclusion (IAD interview) and exclusion (psychotic disorders, neurocognitive deficits, dementia, serious mental delay, current alcohol or drug abuse) criteria. Twenty-one patients of the clinical group were compared with 65 subjects of a control group who were recruited online using IAT. RESULTS IAD patients showed significantly higher scores on the IAT compared to subjects of the control group. Only item 7 (How often do you check your e-mail before something else that you need to do?) showed a significant inverse trend. SCL-90-R anxiety and depression subscale scores and item 19 (How often do you choose to spend more time online over going out with others?) of the IAT were positively correlated with number of weekly hours spent online in IAD patients. CONCLUSION Findings suggest that a misuse of internet, characterized by many hours spent online avoiding interpersonal relationships with real and known people, could be an important criterion in the clinical interview in order to diagnose the IAD. The association between the lost interest in communicating with real people and psychological symptoms such as anxiety and depression could be relevant to detect IAD patients.

Facial emotion recognition deficit in Amnestic Mild Cognitive Impairment and Alzheimer Disease

OBJECTIVES A deficit in facial emotion recognition was described in patients with Alzheimer disease (AD). However, this issue has been underexplored in subjects with amnestic mild cognitive impairment (a-MCI). Thus, the authors aimed to determine whether a deficit in facial emotion recognition is present in a-MCI phase and whether this is intensity dependent. A secondary aim was to investigate relationships between facial emotion recognition and cognitive performances. DESIGN Case-control study. SETTING Memory clinic. PARTICIPANTS Fifty a-MCI patients, 50 mild AD patients, and 50 comparison subjects (COM) were enrolled. MEASUREMENTS Information about facial emotion recognition was obtained from Penn Emotion Recognition Test. The Mental Deterioration Battery was used to measure cognitive impairment. RESULTS Mild AD patients were more impaired in the recognition of almost all emotional stimuli of all intensities than a-MCI and COM subjects. However, there was an increased progression only in low-intensity facial emotion recognition deficit from COM to a-MCI to mild AD patients. In particular, a-MCI subjects differed significantly from COM in low-intensity fearful face recognition performance. This deficit in a-MCI patients was explained by the short-term verbal memory impairment, whereas the same deficit in mild AD patients was explained by the long-term verbal memory impairment. CONCLUSIONS Emotion recognition progresses from a deficit in low-intensity fearful facial recognition in a-MCI phase to a deficit in all intensities and emotions in mild AD. This could be an effect of the progressive degeneration of brain structures modulating emotional processing. An early detection of emotional impairment in MCI phases of dementia may have clinical implications.

The language of schizophrenia: An analysis of micro and macrolinguistic abilities and their neuropsychological correlates

Language disturbance is one of the main diagnostic features in schizophrenia and abnormalities of brain language areas have been consistently found in schizophrenic patients. The main aim of this study was to describe the impairment of micro and macrolinguistic abilities in a group of twenty-nine schizophrenic patients during the phase of illness stability compared to forty-eight healthy participants matched for age, gender and educational level. Microlinguistic abilities refer to lexical and morpho-syntactic skills, whereas macrolinguistic abilities relate to pragmatic and discourse level processing. Secondary aims were to detect the effect of macrolinguistic on microlinguistic ability, and the neuropsychological impairment associated with the linguistic deficit. The linguistic assessment was performed on story-telling. Three narratives were elicited with the help of a single-picture stimulus and two cartoon stories with six pictures each. A modified version of the Mental Deterioration Battery was used to assess selective cognitive performances. A series of t-tests indicated that all the macrolinguistic variables were significantly impaired in schizophrenic patients in at least one of the three story-tellings. Furthermore, the limited impairment found in microlinguistic abilities was influenced by macrolinguistic performance. Multivariate stepwise regression analyses suggested that reduced attention performances and deficit in executive functions were predictors of linguistic impairment. Language production in schizophrenia is impaired mainly at the macrolinguistic level of processing. It is disordered and filled with irrelevant pieces of information and derailments. Such erratic discourse may be linked to the inability to use pragmatic rules and to cognitive deficits involving factors such as attention, action planning, ordering and sequencing.

Clinical features, response to treatment and functional outcome of bipolar disorder patients with and without co-occurring substance use disorder: 1-year follow-up

INTRODUCTION Bipolar disorder patients (BP) with comorbid Substance Use Disorder (SUD) may present clinical features that could compromise adherence and response to pharmacological treatment. The purpose of this study was to examine clinical and psychopathological features of BP with and without comorbid SUD in a real-world setting. METHODS The sample was composed by 131 affective patients. Sixty-five patients were affected by Bipolar Disorder I (BP-I, 49.2%), 29 by Bipolar Disorder II (BP-II, 22.3%) and 37 by Cyclothymic Disorder (CtD, 28.5%), according to DSM-IV. Sixty-six patients were diagnosed for a comorbid SUD. All patients have been submitted to psychometric assessment with Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), Young Mania Rating Scale (YMRS), Global Assessment Scale (GAS), Social Adjustment Self-reported Scale (SASS), Quality of Life Scale (QoL), at baseline and repeated follow-up periods (1, 3, 6, 12 months). RESULTS BP comorbid for SUD were more likely diagnosed as BP-II and CtD and were less likely to present a moderate-severe manic symptomatology. Furthermore, personality disorders were more frequent in SUD patients than in non-comorbid BP. BP with SUD were not different for primary outcome measure (HDRS, HARS, YMRS, GAS) from non-comorbid BP; however, BP with SUD were significantly more impaired in social functioning (SASS) at any stage of the follow-up and poor functioning increased the risk of relapse in substance use during treatment. Finally, SUD comorbidity did not represent a risk factor for treatment drop-out, while in our sample young age, low treatment dosage and BP-I diagnosis were significantly associated with drop-out. DISCUSSION The primary finding of this work is that BP with comorbid SUD are significantly more compromised in social functioning. Second, these patients were less likely to be diagnosed for BP-I and to present a severe manic symptomatology. Finally, we found that the diagnosis of SUD, but young age, low treatment dosage and BP-I diagnosis to be risk factors for treatment drop-out. Physicians should be alert to these differences in their clinical practice.

Alcohol protracted withdrawal syndrome: the role of anhedonia

Aims: The aim of the present study is to characterize the relevance of withdrawal symptoms during the first 12 months of abstinence and their relation to anhedonia and craving. Methods: 102 detoxified subjects meeting clinical criteria for Alcohol Dependence in Remission were recruited at various time since the detoxification and subdivided into four groups according to the length of abstinence (group 1: 15–30 days; group 2: 30–90 days; group 3: 90–180 days; group 4: 180–360). Withdrawal symptomatology was assessed through the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). The Visual Analogue Scale (VAS) for craving, the Snaith–Hamilton Pleasure Scale (SHAPS) and the Subscale for Anhedonia in the Scale for the Assessment of Negative Symptoms (SANSanh) where the other instruments employed. Results: Both anhedonia and withdrawal symptoms were identified in all the groups considered. SHAPS score and VAS for craving showed a significant difference between group 1 and groups 2, 3, and 4. As to CIWA-Ar items, apart from “orientation/clouding of sensorium” that was higher in groups 3 and 4 with respect to both groups 1 and 2, withdrawal symptoms were not significantly different between the periods considered. SHAPS and SANSanh were positively correlated to CIWA-Ar total score, “nausea and vomiting,” and “headache/fullness in head.” Discussion: The results of this study suggest the relevance of protracted withdrawal well beyond the limited period following the abrupt cessation of alcohol intake. The clinical dimension of anhedonia cannot be separated from the other behavioral symptoms of withdrawal and should be considered as part of the same process.