Sara Poletti

Disruption of White Matter Integrity in Bipolar Depression as a Possible Structural Marker of Illness

BACKGROUND Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. METHODS We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. RESULTS Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior-posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. CONCLUSIONS Reduced FA with increased mean and radial diffusivity suggests significant demyelination and/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness.

Functional and structural brain correlates of theory of mind and empathy deficits in schizophrenia

BACKGROUND Patients affected by schizophrenia show deficits in social cognition, with abnormal performance on tasks targeting theory of mind (ToM) and empathy (Emp). Brain imaging studies suggested that ToM and Emp depend on the activation of brain networks mainly localized at the superior temporal lobe and temporo-parietal junction. METHODS Participants included 24 schizophrenia patients and 20 control subjects. We used brain blood oxygen level dependent fMRI to study the neural responses to tasks targeting ToM and Emp. We then studied voxel-based morphometry of grey matter in areas where diagnosis influenced functional activation to both tasks. Outcomes were analyzed in the context of the general linear model, with global grey matter volume as nuisance covariate for structural MRI. RESULTS Patients showed worse performance on both tasks. We found significant effects of diagnosis on neural responses to the tasks in a wide cluster in right posterior superior temporal lobe (encompassing BA 22-42), in smaller clusters in left temporo-parietal junction and temporal pole (BA 38 and 39), and in a white matter region adjacent to medial prefrontal cortex (BA 10). A pattern of double dissociation of the effects of diagnosis and task on neural responses emerged. Among these areas, grey matter volume was found to be reduced in right superior temporal lobe regions of patients. CONCLUSIONS Functional and structural abnormalities were observed in areas affected by the schizophrenic process early in the illness course, and known to be crucial for social cognition, suggesting a biological basis for social cognition deficits in schizophrenia.

Tract-specific white matter structural disruption in patients with bipolar disorder

OBJECTIVES A growing body of evidence suggests that, independent of localized brain lesions, mood disorders can be associated with dysfunction of brain networks involved in the modulation of emotional and cognitive behavior. We used diffusion tensor (DT) tractography to quantify the presence and extent of structural injury to the connections between the amygdala and other brain regions, which included the subgenual, the supragenual and posterior cingulate, the parahippocampal, the orbitofrontal and dorsolateral prefrontal cortices, as well as the insula. METHODS Using a 3.0 Tesla scanner, conventional and DT magnetic resonance imaging sequences of the brain were acquired from 15 adult patients with major depressive disorder (MDD), 15 with bipolar disorder (BD), and 21 age-matched healthy controls. Using FSL software, diffusivity changes of the white matter (WM) fiber bundles belonging to the emotional network were measured. RESULTS Compared to controls and MDD patients, BD patients had significantly decreased average fractional anisotropy, increased average mean diffusivity, and increased average axial and radial diffusivity values in the majority of the WM fiber bundles connecting structures of the anterior limbic network (p-values ranging from 0.002 to 0.040). Medication load did not influence the results with the exception of lithium, which was associated with normal diffusivity values in tracts connecting the amygdala with the subgenual cingulate cortex. CONCLUSIONS We detected specific WM abnormalities, suggestive of disrupted integrity of fiber bundles in the brains of patients with BD. These abnormalities might contribute to understanding both mood dysregulation and cognitive disturbances in BD, and might provide an objective marker to monitor treatment efficacy in this condition.

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-β (GSK3-β). The less active GSK3-β promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-β gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-β promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-β rs334558*C gene-promoter variants, and the long-term administration of the GSK3-β inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.

The Brief Assessment of Cognition in Schizophrenia. Normative data for the Italian population

ObjectiveTo provide normative values for the Italian population for the Brief Assessment of Cognition in Schizophrenia (BACS), a recent brief neuropsychological instrument for the assessment of cognition in patients with schizophrenia.ParticipantsData were collected from 204 healthy adult Italian subjects, stratified by gender, education and age.Measurements and resultsTests included in the BACS are the following: list learning, digit sequencing, verbal fluency, token motor task, symbol-coding and Tower of London. Normative values were established using the Equivalent Scores method in order to enable comparison with other neuropsychological tasks commonly used in the assessment of the Italian population. Performance on the BACS was influenced by the commonest demographic variables such as age and education.ConclusionsThe availability of normative data for the Italian population will increase the usefulness of this test for both clinical and experimental purposes.SommarioNon esistono ad oggi batterie specifiche brevi e facilmente fruibili in lingua italiana per la valutazione del deficit cognitivo dei pazienti con schizofrenia. Lo scopo di questo studio è di tradurre e tarare sulla popolazione italiana la batteria BACS (Brief Assessement of Cognition in Schizophrenia), un breve strumento di screening creato per indagare in modo specifico gli ambiti cognitivi riconosciuti come quelli con le maggiori disfunzioni e correlati ai sintomi della schizofrenia (memoria verbale, velocità e coordinazione psico-motoria, attenzione, funzioni esecutive e fluenza verbale) e che ha mostrato nella validazione in lingua americana una buona correlazione con batterie neuropsicologiche standard e una buona affidabilità testretest. Il campione è costituito da 204 soggetti italiani stratificati per sesso, età e scolarità. I test inclusi nella BACS sono i seguenti: memoria di lista di parole, riordinamento di cifre, fluenza verbale, compito motorio dei gettoni, associazione simboli-numeri e Torre di Londra. I dati normativi sono stati calcolati con il metodo statistico dei Punteggi Equivalenti, con l’obiettivo di rendere possibile il confronto con altri test neuropsicologici usati comunemente in lingua italiana. Le prestazioni alla BACS sono risultate influenzate da variabili demografiche come età e scolarità, confermando i dati presenti in letteratura. La disponibilità di dati normativi per la popolazione italiana ha la potenzialità di aumentare l’utilità di questo test per scopi sia clinici che di ricerca.

Opposite effects of suicidality and lithium on gray matter volumes in bipolar depression.

BACKGROUND Mood disorders are associated with the highest increase of attempted and completed suicide. Suicidality in major depressive disorder and in schizophrenia has been associated with reduced gray matter volumes in orbitofrontal cortex. Lithium reduces the suicide risk of patients with bipolar disorder (BD) to the same levels of the general population, and can increase GM volumes. We studied the effect of a positive history of attempted suicide and ongoing lithium treatment on regional GM volumes of patients affected by bipolar depression. METHODS With a correlational design, we studied 57 currently depressed inpatients with bipolar disorder: 19 with and 38 without a positive history of suicide attempts, 39 unmedicated and 18 with ongoing lithium treatment. Total and regional gray matter volumes were assessed using voxel-based morphometry. RESULTS Total GM volume is inversely correlated with depression severity. A positive history of suicide attempts was associated with higher stress in early life. Suicide attempters showed reduced GM volumes in several brain areas including dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, superior temporal cortex, parieto-occipital cortex, and basal ganglia. Long term lithium treatment was associated with increased GM volumes in the same areas where suicide was associated with decreased GM. CONCLUSIONS Reduced GM volumes in critical cortical areas of suicidal patients could be a biological correlate of an impaired ability to associate choices and outcomes and to plan goal-directed behaviors based on a lifetime historical perspective, which, coupled with mood-congruent depressive cognitive distortions, could lead to more hopelessness and suicide. Lithium could exert its specific therapeutic effect on suicide by acting in the same areas.

Computer-aided neurocognitive remediation as an enhancing strategy for schizophrenia rehabilitation

Cognitive dysfunction is a chronically disabling feature of schizophrenia, associated with limits in obtaining rehabilitation improvements. The purpose of this study is to assess the effectiveness of intensive computer-aided cognitive remediation treatment (CRT) added to a standard rehabilitation treatment (SRT), in enhancing neuropsychological performances and daily functioning in patients with schizophrenia. A 12-week, randomized, controlled, single-blind trial of neurocognitive remediation was carried out on 86 patients with clinically stabilized DSM-IV schizophrenia. Patients were assessed on cognitive and daily functioning before and after either CRT or placebo training that had been added to their SRT. After 3 months the repeated measure ANOVA showed a significant time x treatment interaction for executive function and attention performances and in daily functioning assessment in favour of patients in the SRT+CRT treatment. Results confirmed that cognitive remediation added to the SRT of schizophrenia enhanced its neuropsychological effects and increased the effects of a long-term rehabilitation programme in terms of functional outcomes.

Influence of catechol-O-methyltransferase Val158Met polymorphism on neuropsychological and functional outcomes of classical rehabilitation and cognitive remediation in schizophrenia.

Neurocognitive deficits are recognized as core features of schizophrenia and have a great impact on functional outcome. Recent reports have suggested that a functional polymorphism, Val158Met, of the catechol-O-methyltransferase (COMT) gene, partially influences cognitive performances (mainly cognitive flexibility and working memory) both in schizophrenic patients and in healthy controls, probably by modulating prefrontal dopamine function. While previous studies focused on single evaluation of cognitive functioning, we aimed to analyse the additive effect of COMT genotype and cognitive exercise on dynamic modulation of cognitive performances. We analysed the COMT Val158Met polymorphism in 50 patients with chronic schizophrenia randomly allocated to two treatment conditions for 3 months: standard rehabilitation treatment (SRT) alone and SRT plus specific cognitive exercise of impaired functions. We then divided our sample in four subgroups on the basis of genotype (Val/Val versus Met carriers) and treatment (placebo versus active). We assessed patients with a neuropsychological battery, the Positive and Negative Symptoms Scale (PANSS) and the Quality of Life Scale (QLS) at enrolment, after 3 months of therapy and after further 3 months of follow-up. We found significantly greater improvement of cognitive flexibility performance and QLS total score for Met carriers on active treatment in comparison to Val/Val on placebo. The findings support the hypothesis that COMT polymorphism influences individual capacity to recover from cognitive deficit through rehabilitation therapy after a wider intervention also including deficit-specific cognitive exercise as a potentiating tool.

Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drug-resistant bipolar depression.

BACKGROUND One third of patients with bipolar disorder attempt suicide. Depression in bipolar disorder is associated with drug resistance. The efficacy of antidepressants on suicidality has been questioned. Total sleep deprivation and light therapy prompt a rapid and stable antidepressant response in bipolar disorder. METHOD We studied 143 consecutively admitted inpatients (December 2006-August 2012) with a major depressive episode in the course of bipolar disorder (DSM-IV criteria). Among the 141 study completers, 23% had a positive history of attempted suicide and 83% had a positive history of drug resistance. During 1 week, patients were administered 3 consecutive total sleep deprivation cycles (each composed of a period of 36 hours awake followed by recovery sleep) combined with bright light therapy in the morning for 2 weeks. At admission, patients who had been taking lithium continued it, and those who had not been taking lithium started it. Severity of depression was rated according to the Hamilton Depression Rating Scale (HDRS) (primary outcome measure) and Beck Depression Inventory (BDI). RESULTS Two patients switched polarity. Among the 141 who completed the treatment, 70% achieved a 50% reduction in HDRS score in 1 week, which persisted 1 month after in 55%. The amelioration involved an immediate and persistent decrease in suicide scores soon after the first total sleep deprivation cycle (F3,411 = 42.78, P < .00001). A positive history of suicide attempts was associated with worse early life stress and with worse suicide scores at baseline, but it did not influence response. Patients with current suicidal thinking or planning responded equally well (F3,42 = 20.70, P < .000001). Remarkably, however, nonresponders achieved a benefit, with significantly decreased final scores also including suicidality ratings (F3,120 = 6.55, P = .0004). Self-ratings showed the same pattern of change. Previous history of drug resistance did not hamper response. During the following month, 78 of 99 responders continued to stay well and were discharged from the hospital on lithium therapy alone. CONCLUSIONS The combination of total sleep deprivation, light therapy, and lithium is able to rapidly decrease depressive suicidality and prompt antidepressant response in drug-resistant major depression in the course of bipolar disorder.

Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-β activity

At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3‐βpromoter single‐nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel‐based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3‐βas a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.