Jozarni J. Dlabac-de Lange

Neural correlates of planning performance in patients with schizophrenia — Relationship with apathy

Patients with schizophrenia often suffer from apathy: a quantitative reduction of voluntary, goal-directed behaviors that impairs daily functioning. We hypothesized that schizophrenia patients with high levels of apathy would show decreased activation in brain regions involved in planning and goal-directed behavior. Patients with schizophrenia or psychotic spectrum disorder (n=47) and healthy controls (n=20) performed the Tower of London (ToL) task during fMRI scanning using arterial spin labeling. To investigate the relationship between apathy and planning in patients, a proxy measure of apathy based on the Positive and Negative syndrome Scale was regressed against the task-related brain activation. Brain activation was also compared between patients and healthy controls. Higher levels of apathy were associated with less task-related activation within the inferior parietal lobule precuneus and thalamus. Compared to controls, patients showed lower activation in lateral prefrontal regions, parietal and motor areas, and a higher activation of medial frontal areas. Apathy was related to abnormal activation in thalamus and parietal regions during the ToL task. This supports the hypothesis that impaired function of brain regions involved in planning and goal-directed behavior may underlie apathy in schizophrenia. Moreover, impaired lateral prefrontal activation in schizophrenia patients compared to controls is consistent with the hypofrontality model of schizophrenia. In contrast, stronger medial frontal activation in patients may be related to increased effort to perform a task with conflicting task solutions.

Prefrontal NAA and Glx Levels in Different Stages of Psychotic Disorders : a 3T 1H-MRS Study

H-Magnetic Resonance Spectroscopy (1H-MRS) can offer insights in various neuropathologies by measuring metabolite levels in the brain. In the current study we investigated the levels of glutamate + glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate + glutamic acid (NAA + NAAG; neuronal viability) in the prefrontal cortex of patients with a psychotic disorder and people at Ultra High Risk (UHR) for psychosis. A 1H-MRS spectrum was acquired in 31 patients with a recent onset psychotic disorder and 60 with a chronic state, 16 UHR patients and 36 healthy controls. Absolute metabolite levels were calculated using LCModel with a reference water peak. Groups were compared while taking into account age and partial volume effects. Moreover, we investigated associations with positive and negative symptoms, duration of illness, and antipsychotic treatment in patients. The most notable finding is that chronicity of schizophrenia was related to decreased levels of Glx and NAA. On the other hand, although on an exploratory note, UHR showed increased levels of prefrontal Glx and NAA levels with increasing age. Our results may indicate an initial Glx and NAA increase and subsequent decrease during illness progression that may be related to the neurotoxic effects of glutamate.

Effect of rTMS on brain activation in schizophrenia with negative symptoms: A proof-of-principle study

BACKGROUND Prefrontal cortical dysfunction is frequently reported in schizophrenia and is thought to underlie negative symptoms of schizophrenia. Repetitive Transcranial Magnetic Stimulation (rTMS) can modulate neuronal activity and has been shown to improve negative symptoms in patients with schizophrenia, but the underlying neural mechanism is unknown. OBJECTIVE To examine whether 3weeks of 10Hz rTMS treatment of the bilateral dorsolateral prefrontal cortex (DLPFC) would improve frontal brain activation in patients with negative symptoms of schizophrenia, as measured by functional magnetic resonance imaging (fMRI) during the Tower of London (ToL) task. METHODS 24 patients with the diagnosis of schizophrenia with moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale≥15) participated. Patients were randomized to a 3-week (15day) course of active or sham rTMS. All patients performed the ToL task during fMRI scanning both pre-treatment and post-treatment. Differences in brain activation between the two groups were compared non-parametrically. RESULTS After rTMS treatment, brain activity in the active group increased in the right DLPFC and the right medial frontal gyrus as compared to the sham group. In addition, the groups significantly differed with regard to activation change in the left posterior cingulate, with decreased activation in the active and increased activation in the sham group. CONCLUSIONS Treatment with rTMS over the DLPFC may have the potential for increasing task-related activation in frontal areas in patients with schizophrenia. Effects of different rTMS parameters and fMRI tasks targeting relevant brain circuitry deserve further investigation. TRIAL REGISTRATION Nederlands Trial Register, registration number: NTR1261.

Effect of Bilateral Prefrontal rTMS on Left Prefrontal NAA and Glx Levels in Schizophrenia Patients with Predominant Negative Symptoms: An Exploratory Study

BACKGROUND Prefrontal repetitive Transcranial Magnetic Stimulation (rTMS) may improve negative symptoms in patients with schizophrenia, but few studies have investigated the underlying neural mechanism. OBJECTIVE This study aims to investigate changes in the levels of glutamate and glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate (NAA) in the left dorsolateral prefrontal cortex of patients with schizophrenia treated with active bilateral prefrontal rTMS as compared to sham-rTMS, as measured with 1H-Magnetic Resonance Spectroscopy (1H-MRS). METHODS Patients were randomized to a 3-week course of active or sham high-frequency rTMS. Pre-treatment and post-treatment 1H-MRS data were available for 24 patients with schizophrenia with moderate to severe negative symptoms (Positive and Negative Syndrome Scale (PANSS) negative subscale ≥ 15). Absolute metabolite concentrations were calculated using LCModel with the water peak as reference. To explore the association between treatment condition and changes in concentration of Glx and NAA, we applied a linear regression model. RESULTS We observed an increase of Glx concentration in the active treatment group and a decrease of Glx concentration in the group receiving sham treatment. The association between changes in Glx concentration and treatment condition was significant. No significant associations between changes in NAA and treatment condition were found. CONCLUSIONS Noninvasive neurostimulation with high-frequency bilateral prefrontal rTMS may influence Glx concentration in the prefrontal cortex of patients with schizophrenia. Larger studies are needed to confirm these findings and further elucidate the underlying neural working mechanism of rTMS.

Moderate effects of noninvasive brain stimulation of the frontal cortex for improving negative symptoms in schizophrenia : meta-analysis of controlled trials

Background: Negative symptoms in schizophrenia concern a clinically relevant reduction of goal‐directed behavior that strongly and negatively impacts daily functioning. Existing treatments are of marginal effect and novel approaches are needed. Noninvasive neurostimulation by means of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are novel approaches that may hold promise. Objectives: To provide a quantitative integration of the published evidence regarding effects of rTMS and tDCS over the frontal cortex on negative symptoms, including an analysis of effects of sham stimulation. Methods: Meta‐analysis was applied, using a random effects model, to calculate mean weighted effect sizes (Cohens d). Heterogeneity was assessed by using Cochrans Q and I2 tests. Results: For rTMS treatment, the mean weighted effect size compared to sham stimulation was 0.64 (0.32–0.96; k=22, total N=827). Studies with younger participants showed stronger effects as compared to studies with older participants. For tDCS studies a mean weighted effect size of 0.50 (−0.07 to 1.07; k=5, total N=134) was found. For all frontal noninvasive neurostimulation studies together (i.e., TMS and tDCS studies combined) active stimulation was superior to sham, the mean weighted effect size was 0.61 (24 studies, 27 comparisons, 95% confidence interval 0.33–0.89; total N=961). Sham rTMS (baseline ‐ posttreatment comparison) showed a significant improvement of negative symptoms, d=0.31 (0.09–0.52; k=16, total N=333). Whereas previous meta‐analyses were underpowered, our meta‐analysis had a power of 0.87 to detect a small effect. Conclusions: The available evidence indicates that noninvasive prefrontal neurostimulation can improve negative symptoms. This finding suggests a causal role for the lateral frontal cortex in self‐initiated goal‐directed behavior. The evidence is stronger for rTMS than for tDCS, although this may be due to the small number of studies as yet with tDCS. More research is needed to establish moderator variables that may affect response to neurostimulation and to optimize treatment parameters in order to achieve stable and durable (and thus clinically relevant) effects. HIGHLIGHTSNoninvasive neurostimulation can potentially improve negative symptoms.The effect of lateral prefrontal stimulation on active behavior suggests a causal role.Moderator variables such as intensity of stimulation and duration of illness are relevant.

Effects of bilateral prefrontal rTMS on brain activation during social-emotional evaluation in schizophrenia: A double-blind, randomized, exploratory study

This exploratory study reports on the effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on (prefrontal) brain activity changes during ambiguous emotional evaluation in patients with schizophrenia. Before and after randomly assigned treatment with active and sham rTMS, patients performed the Wall of Faces task during fMRI scanning. fMRI analysis showed that rTMS treatment resulted in reduced activation of striato-fronto-parietal brain areas, while activation increased compared to baseline after sham. Thus, prefrontal rTMS may normalize an increased brain response to ambiguous emotional stimuli, but future studies should confirm these findings.