Mohamed Saoud

Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia.

OBJECTIVE Some 25%–30% of patients with schizophrenia have auditory verbal hallucinations that are refractory to antipsychotic drugs. Outcomes in studies of repetitive transcranial magnetic stimulation suggest the possibility that application of transcranial direct-current stimulation (tDCS) with inhibitory stimulation over the left temporo-parietal cortex and excitatory stimulation over the left dorsolateral prefrontal cortex could affect hallucinations and negative symptoms, respectively. The authors investigated the efficacy of tDCS in reducing the severity of auditory verbal hallucinations as well as negative symptoms. METHOD Thirty patients with schizophrenia and medication-refractory auditory verbal hallucinations were randomly allocated to receive 20 minutes of active 2-mA tDCS or sham stimulation twice a day on 5 consecutive weekdays. The anode was placed over the left dorsolateral prefrontal cortex and the cathode over the left temporo-parietal cortex. RESULTS Auditory verbal hallucinations were robustly reduced by tDCS relative to sham stimulation, with a mean diminution of 31% (SD=14; d=1.58, 95% CI=0.76–2.40). The beneficial effect on hallucinations lasted for up to 3 months. The authors also observed an amelioration with tDCS of other symptoms as measured by the Positive and Negative Syndrome Scale (d=0.98, 95% CI=0.22–1.73), especially for the negative and positive dimensions. No effect was observed on the dimensions of disorganization or grandiosity/excitement. CONCLUSIONS Although this study is limited by the small sample size, the results show promise for treating refractory auditory verbal hallucinations and other selected manifestations of schizophrenia.

Consensus paper of the WFSBP Task Force on Biological Markers: biological markers in depression.

Biological markers for depression are of great interest to aid in elucidating the causes of major depression. We assess currently available biological markers to query their validity for aiding in the diagnosis of major depression. We specifically focus on neurotrophic factors, serotonergic markers, biochemical markers, immunological markers, neuroimaging, neurophysiological findings, and neuropsychological markers. We delineate the most robust biological markers of major depression. These include decreased platelet imipramine binding, decreased 5-HT1A receptor expression, increase of soluble interleukin-2 receptor and interleukin-6 in serum, decreased brain-derived neurotrophic factor in serum, hypocholesterolemia, low blood folate levels, and impaired suppression of the dexamethasone suppression test. To date, however, none of these markers are sufficiently specific to contribute to the diagnosis of major depression. Thus, with regard to new diagnostic manuals such as DSM-V and ICD-11 which are currently assessing whether biological markers may be included in diagnostic criteria, no biological markers for major depression are currently available for inclusion in the diagnostic criteria.

Slow transcranial magnetic stimulation can rapidly reduce resistant auditory hallucinations in schizophrenia

BACKGROUND Almost a quarter of patients with schizophrenia present with resistant auditory verbal hallucinations (AVH), a phenomenon that may relate to activation of brain areas underlying speech perception. Repetitive transcranial magnetic stimulation (rTMS) at 1 Hz reduces cortical activation, and recent results have shown that 1-Hz left temporoparietal rTMS may reduce AVH. The aim of this study was to replicate recent data and investigate whether low-frequency rTMS with a high total stimulation number delivered in a shorter 5-day block produces similar benefit. METHODS Ten right-handed schizophrenia patients with resistant AVH received 5 days of active rTMS and 5 days of sham rTMS (2,000 stimulations per day at 90% of motor threshold) over the left temporoparietal cortex in a double-blind crossover design. The two weeks of stimulation were separated by a 1-week washout period. RESULTS AVH were robustly improved (56%) by 5 days active rTMS, whereas no variation was observed after sham. Seven patients were responders to active treatment, five of whom maintained improvement for at least 2 months. CONCLUSIONS These data confirm the efficiency of low-frequency rTMS applied to the left temporoparietal cortex, compared with sham stimulation, in reducing resistant AVH. This improvement can be obtained in only 5 days without serious initial adverse events.

Attention, motor control and motor imagery in schizophrenia: implications for the role of the parietal cortex.

Many recent models of schizophrenia have attempted to explain the so-called first-rank symptoms in terms of a breakdown in the self-monitoring of thoughts and behaviours. These models have focused on the most common symptom of schizophrenia auditory hallucinations-suggesting that they may represent disordered self-monitoring of internal speech. As such, much attention has been given to the role of the temporal and frontal cortices in the clinical presentation of patients with schizophrenia. In this review, we examine the role of the posterior parietal cortex (PPC) in schizophrenia within the context of recent models of self-monitoring deficits in these patients. Attentional dysfunctions and certain impairments of motor control and motor imagery all point towards the involvement of the parietal cortex in the disorder. In particular, we suggest that patients experiencing passivity phenomena (e.g., delusions of control) may have particular impairments of parietal function related to poor utilisation of forward models of intended actions. We also present a novel hypothesis that suggests differential impairments of the left and right parietal cortices in schizophrenia may help explain many of the first-rank symptoms of the disorder.

Alteration of event related potentials in siblings discordant for schizophrenia

This study was aimed at confirming that auditory event related potential (ERP) abnormalities are indicators of vulnerability to schizophrenia. Auditory ERP performances were assessed at Fz, Cz, and Pz, with an oddball paradigm, in 21 clinically stable patients with schizophrenia, 21 of their healthy biological full siblings and 21 control subjects. The evoked response did not differ between the three groups on N200 waves. Compared to controls, patients with schizophrenia exhibited reduced amplitudes of N100 and P300, and prolonged latency of P300, while their siblings showed prolonged latency of P200 and P300. Among the patients with schizophrenia, ERP abnormalities did not correlate with age, clinical state, duration of illness or antipsychotic treatments. Although other conditions also accounted for alterations of the same type, ERP abnormalities may represent a neurobiological marker of the genetic vulnerability to schizophrenia, independent of phenotypic expression.

Facial Expression and Sex Recognition in Schizophrenia and Depression

Background: Impaired facial expression recognition in schizophrenia patients contributes to abnormal social functioning and may predict functional outcome in these patients. Facial expression processing involves individual neural networks that have been shown to malfunction in schizophrenia. Whether these patients have a selective deficit in facial expression recognition or a more global impairment in face processing remains controversial. Objective: To investigate whether patients with schizophrenia exhibit a selective impairment in facial emotional expression recognition, compared with patients with major depression and healthy control subjects. Methods: We studied performance in facial expression recognition and facial sex recognition paradigms, using original morphed faces, in a population with schizophrenia (n = 29) and compared their scores with those of depression patients (n = 20) and control subjects (n = 20). Results: Schizophrenia patients achieved lower scores than both other groups in the expression recognition task, particularly in fear and disgust recognition. Sex recognition was unimpaired. Conclusion: Facial expression recognition is impaired in schizophrenia, whereas sex recognition is preserved, which highly suggests an abnormal processing of changeable facial features in this disease. A dysfunction of the top-down retrograde modulation coming from limbic and paralimbic structures on visual areas is hypothesized.

Effects of acute metabolic stress on the dopaminergic and pituitary–adrenal axis activity in patients with schizophrenia, their unaffected siblings and controls

A genetically mediated abnormal sensitivity to stress is thought to play a role in the onset, exacerbation and relapse of schizophrenia. In a double blind, placebo-controlled crossover study, peak increases in plasma ACTH (Delta ACTH) and homovanillic-acid, a dopamine metabolite, (Delta HVA) following exposure to a metabolic stressor(2DG) were studied in unaffected siblings of patients with schizophrenia (n=15), their patient relatives (n=15) and healthy controls (n=14). Siblings showed a stress response (both Delta ACTH and Delta HVA) that was significantly greater compared to controls and significantly less pronounced compared to patients. The results suggest that the genetic risk for schizophrenia may be characterized by an enhanced sensitivity to stress.

Auditory event-related potentials and clinical scores in unmedicated schizophrenic patients.

Event-related potentials (ERPs) have been widely examined in schizophrenic patients. However, although neuroleptic medication could be a potentially confounding variable, studies with unmedicated patients are relatively scarce. The present work was undertaken to determine whether ERP abnormalities persist in stabilized schizophrenic patients after drug withdrawal. In addition, ERP amplitudes and latencies were compared with clinical ratings (the Positive and Negative Syndrome Scale, PANSS) by means of Spearman rank order correlation coefficients. The P300 and N200 responses to rare tones and the P200 and N100 responses to frequent tones were recorded in 20 clinically stabilized drug-free schizophrenic patients and 19 age-matched control subjects during a two-tone discrimination task. Major findings were that the schizophrenic patients had reduced P300, N200 and N100 amplitudes and an increased P300 latency. The P300 amplitude was negatively correlated with age in patients. The P200 latency was negatively correlated with the PANSS positive syndrome score. The ERP abnormalities shown in this study appear to be enduring traits of the disorder as they persist in stabilized patients even after drug withdrawal.

Left temporo-limbic and orbital dysfunction in schizophrenia during odor familiarity and hedonicity judgments

Impairments of olfactory processing in patients with schizophrenia (SZ) have been reported in various olfactory tasks such as detection, discrimination, recognition memory, identification, and naming. The purpose of our study was to determine whether impairments in odor familiarity and hedonicity judgments observed in SZ patients during a previous behavioral study are associated with modifications of the activation patterns in olfactory areas. Twelve SZ patients, and 12 healthy comparison (HC) subjects, were tested using the H2(15)O-PET technique and 48 different odorants delivered during 8 scans. In addition to an odorless baseline condition, they had either to detect odor, or to judge odor familiarity or hedonicity, giving their responses by pressing a button. Regional cerebral blood flows during olfactory conditions were compared with those for baseline condition. Between-group analyses were then performed, and completed by regions of interest analyses. Both groups had equivalent ability for the detection of suprathreshold odorants, but patients found odors less familiar, and pleasant odors less pleasant than HC subjects. These behavioral results were related to functional abnormalities in temporo-limbic and orbital olfactory regions lateralized in the left hemisphere: the posterior part of the piriform cortex and orbital regions for familiarity judgments, the insular gyrus for hedonicity judgments, and the left inferior frontal gyrus and anterior piriform cortex/putamen region for the three olfactory tasks. They mainly resulted from a lack of activation during task conditions in the SZ patients. These data could explain olfactory disturbances and other clinical features of schizophrenia such as anhedonia.

Effects of Fronto-Temporal Transcranial Direct Current Stimulation on Auditory Verbal Hallucinations and Resting-State Functional Connectivity of the Left Temporo-Parietal Junction in Patients With Schizophrenia

Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring.