Olanzapine plus fluoxetine treatment increases Nt-3 protein levels in the rat prefrontal cortex

Evidence is emerging for a role for neurotrophins in the treatment of mood disorders. In this study, we evaluated the effects of chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the rat brain. Wistar rats received daily injections of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25 mg/kg) for 28 days, and we evaluated for BDNF, NGF and NT-3 protein levels in the prefrontal cortex, hippocampus and amygdala. Our results showed that treatment with fluoxetine and olanzapine alone or in combination did not alter BDNF in the prefrontal cortex (p = 0.37), hippocampus (p = 0.98) and amygdala (p = 0.57) or NGF protein levels in the prefrontal cortex (p = 0.72), hippocampus (p = 0.23) and amygdala (p = 0.64), but NT-3 protein levels were increased by olanzapine 6 mg/kg/fluoxetine 25 mg/kg combination in the prefrontal cortex (p = 0.03), in the hippocampus (p = 0.83) and amygdala (p = 0.88) NT-3 protein levels did not alter. Finally, these findings further support the hypothesis that NT-3 could be involved in the effect of treatment with antipsychotic and antidepressant combination in mood disorders.     

Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder

There is evidence that major psychiatric discords such as schizophrenia (SZ) and bipolar disorder (BD) are associated with dysregulation of synaptic plasticity with downstream alterations of neurotrophins. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as promoting the survival, differentiation, and plasticity of neurons. Variants in the BDNF gene increase the risk of SZ and bipolar disorder. Chronic administration of drugs used to treat SZ and BD, such as lithium, valproate, quetiapine, clozapine, and olanzapine, increases BDNF expression in rat brain. To examine serum BDNF, three groups of chronically medicated DSM-IV SZ patients, on treatment with clozapine (n = 27), typical (n = 14), and other atypical antipsychotics (n = 19), 30 euthymic BD patients, and 26 healthy control had 5 ml blood samples collected by venipuncture. Serum BDNF levels were significantly higher in SZ patients (p < 0.001) when compared to either controls or euthymic BD patients. Increased BDNF in SZ patients might be related to the course of illness or to treatment variables. Prospective studies are warranted.     

Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes

Genetic and pharmacological studies have suggested that brain-derived neurotrophic factor (BDNF) may be associated with the pathophysiology of bipolar disorder (BD). The present study investigated serum BDNF levels in manic, depressed, euthymic BD patients and in matched healthy controls, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum BDNF levels were decreased in manic (p = 0.019) and depressed (p = 0.027) BD patients, as compared with euthymic patients and controls. Serum BDNF levels were negatively correlated with the severity of manic (r = −0.37, p = 0.005) and depressive (r = −0.30, p = 0.033) symptoms. These findings further support the hypothesis that the BDNF signaling system may play a role in the pathophysiology of BD.     

State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: A meta-analytic study

Evidence has suggested a role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of bipolar disorder (BD). Recent studies have examined BDNF levels in BD patients, but showed inconsistent results. In current study, meta-analyses by random-effects model were performed to compare blood BDNF levels between BD patients and healthy controls, and examine patients based on different affective status (manic, depressed, or euthymic state). Fifteen studies from 10 citations were included into the analysis. Pooling of results from all studies indicated that, overall, patients with BD had a lower level of BDNF than healthy controls (p = 1 × 10⁻⁴). But when separating these studies based on different affective status, it showed that the significance existed only when comparing patients in manic (p = 0.0008) or depressed (p = 0.02) state with controls, but not in euthymic state (p = 0.25). In addition, BDNF level was significantly increased after pharmacological treatment of manic state (p = 0.01). These findings indicate that BDNF levels are abnormally reduced in manic and depressed states of BD, and the reduced level in manic state increases after treatment. They suggest a role of blood BDNF level as a state-dependent biomarker of bipolar disorder.     

BDNF as an effect modifier for gender effects on pain thresholds in healthy subjects

BDNF is an important marker of neuronal plasticity. It has also been associated with pain processing. Increased BDNF levels are observed in chronic pain syndromes. In order to understand the role of BDNF associated with other factors such as gender on experimental pain we aimed to determine whether experimental heat or pressure pain threshold is correlated with brain derived neurotrophic factor (BDNF) level, gender and age. Heat pain threshold and pressure pain threshold were measured in 49 healthy volunteers (27 females). The multivariate linear regression models (on heat and pressure pain thresholds) revealed a significant effect of gender (p = 0.001 for both models), serum BDNF (p < 0.004 for both models) and interaction between BDNF and gender (<0.001 for both models). In fact, when adjusting for BDNF levels and age, heat and pressure pain thresholds were significantly reduced in women as compared to men (p < 0.001 for both models). These effects were not observed when gender was analyzed alone. These finding suggests that experimental heat and pressure pain threshold is gender-related and BDNF dependent. In fact BDNF has a facilitatory effect on pain threshold in females but has an opposite effect in males; supporting the notion that BDNF is an effect modifier of the gender effects on pain threshold in healthy subjects.     

Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder

Background

The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders.

Methods

We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n = 15 each).

Results

While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P = 0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P = 0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases.

Limitations

On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant.

Conclusions

Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease.     

Spike-timing-related plasticity is preserved in Parkinson's disease and is enhanced by dopamine: Evidence from transcranial magnetic stimulation

We sought to investigate the effects of dopamine on motor cortical plasticity in Parkinson's disease (PD) using a novel interventional transcranial magnetic stimulation protocol that targets spike-timing-dependent plasticity (iTMS). Six patients (3F, mean age 62 years) with mild-moderate PD (mean disease duration 6 years, UPDRS-off 13, UPDRS-on 3, H&Y stage 2, daily levodopa dosage 450 mg) were studied off and on levodopa on separate days. Paired TMS pulses at resting motor threshold with an inter-stimulus interval of 1.5 ms were given over the hand area of the motor cortex for 20 min at 0.2 Hz. Single-pulse motor evoked potential (MEP) amplitude and visually cued simple reaction time (SRT) were measured before and after iTMS. When on levodopa, MEP amplitude increased to 278 ± 36% of baseline (p < 0.01), and when off levodopa to 157 ± 13% of baseline (p = 0.02). All patients showed a significantly greater increase in MEP amplitude when on levodopa than off levodopa (p = 0.01). SRT was reduced to 95% baseline after iTMS off levodopa (p = 0.02), but did not change on levodopa. These findings indicate that motor cortex plasticity to iTMS is preserved in mild-moderate PD. The effects of this spike-timing-related TMS protocol on cortical excitability were consistent and were enhanced by levodopa. The results support the important role of dopamine in regulating synaptic plasticity and justify a larger crossover study to assess the therapeutic effects of iTMS in PD.     

Brain-derived neurotrophic factor serum levels before and after treatment for acute mania

Accumulating evidence suggests that reduced levels of brain-derived neurotrophic factor (BDNF) in acute mood episodes may play an important role in the pathophysiology of bipolar disorder (BD). In order to assess changes in BDNF serum levels in BD patients before and after treatment for acute mania, ten bipolar patients were prospectively examined at inpatient unit admission and discharge. Diagnoses were made using the Structured Clinical Interview for DSM-IV, SCID-I. Serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were decreased in BD patients during mania when compared to controls (p = 0.013) but this difference was no longer significant after treatment (p = 0.126). A sharp increase in BDNF levels was found after treatment of the episode of acute mania (p = 0.010). These findings suggest that the changes in BDNF serum levels may be associated with treatment response in acute mania. Further studies designed to validate the use of BDNF as a marker of treatment response in bipolar disorder are warranted.     

Increased plasma brain-derived neurotrophic factor levels in chronic smokers following unaided smoking cessation

Recent animal studies have suggested an association between nicotine and alterations in brain-derived neurotrophic factor (BDNF) expression levels. However, the role of BDNF in humans with nicotine dependence has not yet been investigated. In this study, we explored the differences in the plasma BDNF levels of chronic smokers and healthy nonsmokers, and we investigated the changes in plasma BDNF levels in chronic smokers following unaided smoking cessation. Forty voluntary participants (20 smokers and 20 nonsmokers) were enrolled in this study. We measured the plasma BDNF levels at baseline (both groups) and at the end of the two-month study period (smoker group only) using an enzyme-linked immunosorbent assay. A total of 12 smokers (60.0%) completed the two-month study. ANCOVA with age and body mass index as covariates showed that the baseline plasma BDNF levels in smokers were significantly lower than those in nonsmokers (F = 4.626, p = 0.038). The plasma BDNF levels in the smokers significantly increased from baseline after the two-month smoking cessation period (Z = −3.059, p = 0.002). These findings suggest that BDNF may play a role in the pathophysiology of smoking behavior.     

Changes in plasma brain-derived neurotrophic factor levels in smokers after smoking cessation

Several studies have reported that brain-derived neurotrophic factor (BDNF) might be associated with nicotine dependence. However, there are few studies on BDNF levels in humans with nicotine dependence. In the present study, we compared the differences in plasma BDNF levels in patients with nicotine dependence and in healthy nonsmokers, and we investigated serial changes in plasma BDNF levels in patients with nicotine dependence following smoking cessation. Forty-five voluntary smokers and 66 nonsmokers were recruited in this study. Of the 45 smokers, 12 were taking varenicline, 21 were using a nicotine patch, and 12 were unaided in their cessation effort by their own choice. Plasma BDNF levels were measured at baseline using an enzyme-linked immunosorbent assay (both smokers and nonsmokers) and at weeks 4 and 12 after smoking cessation (abstinent smokers only). A total of 19 smokers were able to remain abstinent during the entire study period. Baseline plasma BDNF levels were significantly lower in smokers compared to nonsmokers (F = 4.410, p = 0.002). The plasma BDNF levels in the abstinent smokers significantly increased from baseline after 4 weeks of smoking cessation (z = −2.86, p = 0.004) but had a tendency of decrease in the period between weeks 4 and 12. We could not find differences in the plasma BDNF levels among the three smoker subgroups at week 12 following cessation. Changes in plasma BDNF levels might be related to the process of abstinence and the pathophysiology of nicotine dependence.     

Differential hippocampal neuron density between inbred Roman high- (low anxious) and low-avoidance (high anxious) rats

The inbred Roman low- (RLA-I) and high-avoidance (RHA-I) rats used in this study were initially selected and bred for extremely poor vs. rapid acquisition of active two-way avoidance behavior in the shuttle box. As a result of the selection for divergent avoidance acquisition, clear behavioral differences have been found between RHA and RLA rats in a variety of tasks related to anxiety and conflict. In rats of these two strains/lines previous brain studies have been performed, specifically in the striatum, the mesencephalic dopaminergic areas and the prefrontal cortex, as these brain areas are the classical ones for their critical role in sensitization and may play a role in the well-characterized anxiety response. In this study we analyzed, in RHA and RLA groups (N = 5 each), the density of NeuN neurons counterstained with toluidine blue in the cingulate cortex (subdivision 1) and the hippocampus (CA1, CA2 and CA3). A statistical difference was found in the density of neurons of CA1 and CA2 (p = 0.047 in both) and in the total density of the hippocampus (p = 0.009). Contrary to our expectations, significant strain differences for the density of neurons in the cingulate cortex were not found. The relationship between those differences in the hippocampus and the between-strain differences in anxiety and in learning processes depending on anxiety are discussed.     

Quantitative analysis of the 4977-bp common deletion of mitochondrial DNA in postmortem frontal cortex from patients with bipolar disorder and schizophrenia

Several reports have suggested a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. We have focused on the relationship between deleted mitochondrial DNA (mtDNA) and bipolar disorder. To investigate this relationship, we developed a methodology for quantification of the common 4977-bp deletion of mtDNA based on real-time polymerase chain reaction with SYBR Green. In this study, we assessed accumulation of the common deletion in postmortem frontal cortex from 147 individuals (48 controls, 49 patients with bipolar disorder, 50 patients with schizophrenia). We demonstrated age-dependent accumulation of the common deletion of mtDNA (p = 1.09E−10). Females showed significantly higher accumulation of the deletion than did males (p = 0.002). There was no significant association between accumulation and the two studied major mental disorders in the frontal cortex (p > 0.2). However, there was no statistically significant correlation between the common deletion and aging in female patients with bipolar disorder (p = 0.133), and no significant sex difference in patients with bipolar disorder (p = 0.509). These results indicate that aging and sex have effect on accumulation of the common deletion of mtDNA in the prefrontal cortex depending on the diagnosis.     

Male specific association between the 5-HTR6 gene 267C/T SNP and suicide in the Portuguese population

Serotonergic system dysfunction has been implicated in the etiology of suicide. A large number of genetic studies have focused on the potential involvement of genes coding for components of serotonergic system in suicidal behavior. However, other genes belonging to this system remain to be investigated or have been poorly studied, as is the case of the 5-HT6 receptor (5-HTR6) gene. In this study, we investigated the potential association between the 5-HTR6 gene 267C/T SNP and suicide in a Portuguese population. Blood samples were collected from 179 suicide victims and 189 controls. Genotypes for the 5-HTR6 gene 267C/T SNP were obtained with the restriction enzyme Rsa I. A tendency was found for genotype association between this polymorphism and suicide, but the differences were not statistically significant (χ² = 5.374, df = 2, p = 0.068). However, a gender-specific association was detected when comparing the genotype distribution between male suicide victims and male controls (χ² = 6.988, df = 2, p = 0.030), suggesting that this SNP might have a role in the etiology of suicide in male subjects in the Portuguese population.     

Upregulation of acid-sensing ion channel 1 protein expression by chronic administration of cocaine in the mouse striatum in vivo

Acid-sensing ion channels (ASICs) are ligand-gated cation channels activated by a drop in extracellular pH. They are enriched in the mammalian brain with a high synaptic density. Accumulating evidence suggests that ASIC1 contributes to synaptic activity related to learning/memory and fear conditioning, and also plays critical roles in neurodegenerative diseases. In this study, we explored the effect of the psychostimulant, cocaine, on protein expression of ASICs in the mouse forebrain in vivo. We found that chronic systemic injection of cocaine (20 mg/kg, once daily for 5 consecutive days; 14 days of withdrawal) increased ASIC1, but not ASIC2, protein levels in the striatum, including the dorsal (caudate putamen) and the ventral (nucleus accumbens) striatum. No significant changes in ASIC1 or 2 protein levels in the median prefrontal cortex and the hippocampus were observed following the chronic cocaine administration. These data demonstrate that chronic cocaine exposure can upregulate ASIC expression in the striatum in a subunit-selective manner.     

Cerebellar neurometabolite abnormalities in pediatric attention/deficit hyperactivity disorder: A proton MR spectroscopic study

We designed a case–control proton magnetic resonance spectroscopic study comparing the cerebellar and prefrontal regions of a group of 17 ADHD (attention deficit/hyperactivity disorder) medicated children and a group of 17 control children matched for laterality, gender and age. As we had found decreased gray matter volume in the right prefrontal region and the left cerebellar hemisphere in a previous voxel-based morphometry study conducted on an independent ADHD sample, we tested the hypothesis that these regions should show neurometabolite abnormalities. MRI (magnetic resonance imaging) was performed with a 1.5 T system; spectral acquisition was performed with a single-voxel technique and a PRESS sequence. Two volumes of interest were selected in the right prefrontal region and the left cerebellar hemisphere. NAA (N-acetylaspartate), Cre (creatine), Cho (choline), MI (myo-inositol) and Glx (glutamate-glutamine) resonance intensities were absolutely quantified. In the left cerebellar hemisphere, ADHD children showed significant decreased MI and NAA absolute concentrations with high effect sizes (p = 0.004, ES = 1.184; p = 0.001, ES = 1.083). The diminished absolute concentration of the NAA could be related to a gray matter volume decrease in the same cerebellar region found in the previous voxel-based morphometry MRI study, while the reduced MI absolute concentration could express a decreased glial density. This is the first proton MR spectroscopic study examining the cerebellum and it provides additional support for the role of cerebellum in the ADHD neurobiology.     

Novel allelic variants in the human serotonin transporter gene linked polymorphism (5-HTTLPR) among depressed patients with suicide attempt

A polymorphism in the serotonin transporter gene (5-HTTLPR) is being extensively studied for association with suicidal behavior. A new allelic variant within the 5-HTTLPR polymorphism was described but it has not been thoroughly analyzed in the recent literature. The SNP functional analysis demonstrated that the A variant of the L allele (L_A) produces high levels of mRNA and that the G variant (L_G) is equivalent to the S allele. Our aims were to compare the frequency of 5-HTTLPR alleles in 94 depressed patients who attempted suicide compared to 94 controls free of psychiatric disorder, including the embedded SNP rs25531. Using the biallelic classification, our sample contained 62 (33%) LL, 76 (40.4%) LS, and 50 (26.6%) SS individuals. Using the functional classification system, our sample contained 43 (22.5%) L’L’, 84 (44.7%) L'S’, and 61 (32.4%) S'S’ individuals, with no significant differences between cases and controls in genotypic tests in either biallelic (χ² = 2.543; df = 2; p = 0.280) and functional models (χ² = 2.995; df = 2; p = 0.228). The minor allele frequency (MAF) – the S allele – did not show any distributional difference between cases and controls using biallelic classification system 0.51 vs. 0.43, (OR = 1.41; CI95% 0.94 to 2.12; p = 0.121). Also the S’ allele of the functional classification system did not show any distributional difference between the two groups 0.59. vs. 0.51 (OR = 1.35; CI95% 0.90 to 2.03; p = 0.178). This study provided the possibility of a re-analysis of novell 5-HTTLPR functional variants identified within L allele that alters its mRNA production and thus changes its functionality. We could not find any association between both biallelic and functional 5-HTTLPR in depressed patients with suicide attempt, being the small sample size an important limitation for these results. In conclusion, we can suggest that despite the several studies in this issue, the exact effect and role of 5-HTTLPR in genetics of suicide is still unclear and should be better investigated for future studies.     

The concentrations of serum,plasma and platelet BDNF are all increased by treadmill VO2max performance in healthy college men

The most current human-based studies in which brain-derived neurotrophic factor (BDNF) levels in the peripheral blood system are analyzed use it as an indicator that represents BDNF levels in the CNS. However, whether circulating BDNF (serum and plasma) is positively or inversely associated with cardiorespiratory fitness levels (VO_2max) is still controversial, and no study has done to investigate exercise effects on the concentration of BDNF stored in circulating platelets which, in fact, store a large amount of circulating BDNF. Thus, the purpose of this study was to determine the relation between VO_2max and all circulating BDNF levels (serum, plasma and platelets) in college male students (N = 18; age, 19 ± 1 years; height, 173.22 ± 7.65 cm; weight, 78.25 ± 14.25 kg; body fat percent, 13.82 ± 5.68%). Dual X-ray energy absorptiometry whole body scan was used to measure their body composition. After the overnight fast, all participants were performed VO_2max test, and their blood was collected at rest and immediately after the exercise. Our data resulted in significant increases in platelet counts and serum, plasma and platelet BDNF levels immediately after the exercise (p < 0.01). VO_2max had a significant negative correlation with serum BDNF, plasma BDNF and platelet BDNF at rest (p < 0.05) but a significant positive correlation with serum, plasma BDNF, and platelet BDNF immediately after the exercise (p < 0.01). However, our data show no correlation between VO_2max and platelet count both at rest and immediately after the exercise. In conclusion, this is the first study showing that basal BDNF levels are inversely correlated with cardiorespiratory fitness levels but that the inverse correlations turn into positive correlations with all circulating BDNF levels immediately after the exercise. Moreover, it is the first time to provide evidence that platelet BDNF levels are also positively affected by the exercise. However, future studies will be needed to investigate what tissues provide BDNF into the circulating system and to elucidate the role of circulating BDNF.     

Circulating levels of GDNF in bipolar disorder

Neurotrophic factors regulate the survival and growth of neurons, and influence synaptic efficiency and plasticity. Several studies suggest the existence of a relationship between changes in neurotrophic levels and bipolar disorder (BD). The glial cell-line derived neurotrophic factor (GDNF) influences monoaminergic neurons and glial cells, but its role in BD patients is controversial. In order to elucidate it we evaluated plasma levels of GDNF in a sample of 70 BD patients (35 in mania and 35 in euthymia) and compared with 50 healthy controls matched for age, gender and educational levels. GDNF plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were assessed by a Mini-International Neuropsychiatric Interview (MINI-plus), Young Mania and Hamilton Depression Rating Scales. Plasma GDNF levels were significantly increased in BD patients in euthymia compared with BD patients in mania and healthy controls (p < 0.05). GDNF plasma levels were correlated with age (ρ = 0.30, p < 0.05) and negatively correlated with manic symptoms in BD patients (ρ = −0.54, p < 0.05). Our results provide evidence that peripheral levels of GDNF are related with different mood states in BD, reinforcing the involvement of neurotrophic factors in its physiopathology.     

Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): A pilot study in drug resistant depressed patients

Refractory depression is a highly debilitating mental condition that originates major social and economic burden. About 50% of the patients experience a chronic course of illness and up to 20% show an insufficient response to drug treatments. Electroconvulsive therapy (ECT) is the most effective treatment method in refractory depression, although its mechanism of action is still unknown. Brain-derived neurotrophic factor (BDNF) is decreased in depressive episodes, and increases with antidepressant treatment, being suggested as a biomarker of response to ECT. We report the findings of a study on the effects of ECT on BDNF and clinical outcomes in a group of drug resistant depressive patients before and after ECT. The patients post-ECTs have shown an important improvement of depressive symptomatology on the HDRS (p = 0.001), of psychotic features on the BPRS (p = 0.001) and of the severity of illness on the CGI (p = 0.001). There were no changes in the serum BDNF before and after the ECT treatment (p = 0.89). These results do not support the hypothesis that the clinical improvement following ECT is due to changes in the BDNF.     

Riluzole effect on occipital cortex: A structural and spectroscopy pilot study

Background

To investigate the mechanism underlying the anxiolytic properties of riluzole, a glutamate-modulating agent, we previously studied the effect of this drug on hippocampal N-acetylaspartate (NAA) and volume in patients with generalized anxiety disorder (GAD). In the same cohort, we now extend our investigation to the occipital cortex, a brain region that was recently implicated in the antidepressant effect of riluzole.

Methods

Fourteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. The healthy group did not receive riluzole treatment. Both groups underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ) were used as the primary and secondary outcome measures, respectively.

Results

At baseline, we found clusters of increased cortical thickness in the occipital region in GAD compared to healthy subjects. In the right hemisphere, 8 weeks of treatment reduced occipital cortical thickness in the GAD group (t = 3.67, p = 0.004). In addition, the improvement in HAM-A scores was negatively correlated with post-treatment right occipital NAA (r = −0.68, p = 0.008), and with changes in NAA levels (r = −0.53, p = 0.051). In the left hemisphere, we found positive associations between changes in occipital cortical thickness and improvement in HAM-A (r = 0.60, p = 0.04) and PSWQ (r = 0.62, p = 0.03).

Conclusion

These pilot findings implicate the occipital cortex as a brain region associated with pathology and clinical improvement in GAD. In addition, the region specific effect of riluzole implies a distinct pathophysiology in the occipital cortex – compared to other, previously studied, frontolimbic brain structures.