Frontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuum.

Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signalling or impaired top-down cortical regulation. We used spectral dynamic causal modelling of resting-state functional MRI to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naïve first-episode psychosis patients and 23 controls and an independent sample of 36 patients with established schizophrenia and 100 controls. We also investigated the association between FST effective connectivity and striatal 18F-DOPA uptake in an independent healthy cohort of 33 individuals who underwent concurrent functional MRI and PET. Using a posterior probability threshold of 0.95, we found that midbrain and thalamic connectivity were implicated as dysfunctional across both patient groups. Dysconnectivity in first-episode psychosis patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in established schizophrenia patients. In the healthy 18F-DOPA cohort, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits to those associated with psychotic symptom severity in patients. Overall, our findings indicate that subcortical dysconnectivity is evident in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signalling are closely related to striatal dopamine synthesis capacity, which is a robust marker for psychosis.

Staged treatment and acceptability guidelines in early psychosis study (STAGES): A randomized placebo controlled trial of intensive psychosocial treatment plus or minus antipsychotic medication for first-episode psychosis with low-risk of self-harm or aggression. Study protocol and baseline characteristics of participants.

AIM: It is now necessary to investigate whether recovery in psychosis is possible without the use of antipsychotic medication. This study will determine (1) whether a first-episode psychosis (FEP) group receiving intensive psychosocial interventions alone can achieve symptomatic remission and functional recovery; (2) whether prolonging the duration of untreated psychosis (DUP) in a sub-group according to randomisation will be associated with a poorer outcome and thereby establish whether the relationship between DUP and outcome is causative; and (3) whether neurobiological changes observed in FEP are associated with the psychotic disorder or antipsychotic medication. Baseline characteristics of participants will be presented. METHODS: This study is a triple-blind randomized placebo-controlled non-inferiority trial. The primary outcome is the level of functioning measured by the Social and Occupational Functioning Assessment Scale at 6 months. This study is being conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne and includes young people aged 15 to 24 years with a DSM-IV psychotic disorder, a DUP less than 6 months and not high risk for suicide or harm to others. Strict discontinuation criteria are being applied. Participants are also undergoing three 3-Tesla-MRI scans. RESULTS: Ninety participants have been recruited and baseline characteristics are presented. CONCLUSIONS: Staged treatment and acceptability guidelines in early psychosis will determine whether antipsychotic medications are indicated in all young people with a FEP and whether antipsychotic medication can be safely delayed. Furthermore, the relative contribution of psychotic illness and antipsychotic medication in terms of structural brain changes will also be elucidated. The findings will inform clinical practice guidelines.

Functional MRI study of gender effects in brain activations during verbal working memory task.

Neuroimaging methods have been used to study differences of brain function between males and females. Differences in working memory have been also investigated, but results of such studies are mixed with respect to behavioral data, reaction times and activated brain areas. We tried to analyze functional MRI data acquired during the working memory task and search for differences of brain activation between genders. 20 healthy right-handed volunteers (10 males and 10 females) participated in the study. All of them were university students or fresh graduates. Subjects underwent block designed verbal working memory task (Item Recognition Task) inside the MRI scanner. Standard single-subject pre-processing and group fMRI analyses were performed using the FEAT software from FSL library. In the behavioral data, there was no statistically significant difference in the number of correct responses during the task. The task activated similar bilateral regions of frontal, parietal, temporal and occipital lobes, basal ganglia, the brainstem and in the cerebellum, which corresponds to the previous verbal working memory neuroimaging research. In direct comparison, there was no statistically significant difference in brain activation between small samples of male and female young healthy volunteers.

Internet-based cognitive behavioural therapy for young people with suicide-related behaviour (Reframe-IT): a randomised controlled trial.

BACKGROUND: Suicide-related behaviours are common in young people and associated with a range of negative outcomes. There are few evidence-based interventions; however, cognitive behavioural therapy (CBT) shows promise. Internet delivery of CBT is popular, with potential to increase reach and accessibility. OBJECTIVE: To test the effectiveness of an internet-based CBT program (Reframe-IT) in reducing suicide-related behaviours, depression, anxiety, hopelessness and improving problem solving and cognitive and behavioural skills in school students with suicide-related behaviours. METHODS: A parallel randomised controlled trial testing the effectiveness of Reframe-IT plus treatment as usual (TAU) compared with TAU alone in reducing suicidal ideation, suicide attempts, depression, hopelessness, symptoms of anxiety, negative problem orientation and cognitive and behavioural skill acquisition was undertaken. We recruited students experiencing suicidal ideation from 18 schools in Melbourne, Australia, between August 2013 and December 2016. The intervention comprised eight modules of CBT delivered online over 10 weeks with assessments conducted at baseline, 10 weeks and 22 weeks. FINDINGS: Only 50 of the planned 169 participants were recruited. There were larger improvements in the Reframe-IT group compared with the TAU group for the primary outcome of suicidal ideation (intervention -61.6, SD 41.6; control -47.1, SD 42.3, from baseline to 22-week follow-up intervention); however, differences were non-significant (p=0.593). There were no increases in distress in the majority of participants (91.1%) after completion of each module. Changes in depression and hopelessness partly mediated the effect of acquisition of CBT skills on suicidal ideation. CONCLUSIONS: The trial was underpowered due to difficulties recruiting participants as a result of the complex recruitment procedures that were used to ensure safety of participants. Although there were no significant differences between groups, young people were safely and generally well engaged in Reframe-IT and experienced decreases in suicidal ideation and other symptoms as well as improvements in CBT skills. The study is the first online intervention trial internationally to include young people demonstrating all levels of suicide risk. CLINICAL IMPLICATIONS: Integration of internet-delivered interventions for young people with suicide-related behaviour may result in reductions in these behaviours. Further research is needed, but researchers should feel more confident about being able to safely undertake research with young people who experience these behaviours. TRIAL REGISTRATION NUMBER: ACTRN12613000864729.

[Influence of Cervical Spondylotic Spinal Cord Compression on Cerebral Cortical Adaptation. Radiological Study]. / Vliv cervikální spondylogenní mísní komprese na korové funkce mozku. Radiologická studie.

PURPOSE OF THE STUDY: The aim of the study was to measure the sensorimotor brain adaptation activity, shown on functional magnetic resonance images (fMRI), in relation to the degree and extent of spinal cord compression or cervical spondylotic myelopathy (CSM) detected by cervical spine MRI. MATERIAL AND METHODS: Twenty-one patients (average age, 57 years; 9 men and 12 women) with anterior cervical cord compression detected on cervical MRI scans were included. On the images, the degree of spinal canal stenosis, the spinal cord compression based on the antero-posterior diameter of the spinal canal and on transverse areas of the cervical spinal cord and cervical spinal canal, and changes in spinal cord signal intensity were identified. Clinical examination included neurological status, Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI) and pain intensity assessment using the Visual Analogue Scale (VAS). Electrophysiological tests involving motor evoked and sensory evoked potential (MEP and SEP) recording were conducted and, using fMRI, brain activity during movement of both arms was measured. Based on the transverse spinal cord area of above or below 70 mm2, the patients were placed into two subgroups. According to changes in spinal cord signal intensity, the patients were included into three subgroups with normal findings, incipient myelopathy and advanced myelopathy, respectively. Surgery was carried out from the anterior approach and involved cervical disc replacement. All examinations were performed again at 6 months after surgery. Pre- and post-operative results were compared within each set of subgroups and statistically evaluated. RESULTS: The average pre-operative values were found to increase post-operatively as follows: from 6.4 mm to 8.9 mm (by 39%) for the antero-posterior diameter of the spinal canal; from 129.3 mm2 to 162.8 mm2 (by 26%) for the transverse area of the spinal canal; from 72.6 mm2 to 87.4 mm2 (by 20%) for the transverse spinal cord area; and from 16.3 to 17.4 for the JOA score. The average NDI decreased from 37.9 to 23.7 and the average VAS fell from 6.4 to 1.5. All patients with the change of spinal cord signal that indicated advanced myelopathy also had relevant pathological findings on MEP/SEP examination and this was statistically significant. There was no significant difference in fMRI scans between the two subgroups established on the basis of transverse spinal cord area measurements. In the patients grouped by a change in spinal cord signals, the pre-operative fMRI showed a significantly higher brain activation volume in the subgroup with advanced myelopathy, as compared with the two other subgroups. Surgery resulted in a moderate reduction of the volume of active brain tissue in all three groups. In the patients with advanced myelopathy evaluated in relation to local changes in brain activation, surgery led to a significant decrease in activation volumes in the ipsilateral primary motor cortex and cerebellar hemisphere. There was also a significant increase in activation of the contralateral supplementary motor cortex. DISCUSSION: It is evident that the brain responds to spinal cord damage by increased activity, but with a certain delay. A slightly altered spinal cord signal intensity, such as in incipient myelopathy, apparently does not result in brain activation. On the other hand, significant changes in signal intensity in advanced myelopathy are related to deterioration of spinal cord function, as shown by MEP and SEP examination results, and an increase in both the volume and intensity of cortical motor activation as a compensation mechanism for myelopathy. CONCLUSIONS Hyperintense spinal cord signals on T2-weighted images correlated with the pathological spinal cord function detected by electrophysiological test in all patients. The transverse spinal cord area (around 70 mm2) showed no significant correlation with either sensory and motor brain adaptations or the results of SEP and MEP testing; therefore, as a criterion for indication to surgery it is of no value. The patients with advanced myelopathy, as detected by spinal cord MRI, had a significantly higher pre-operative cortical motor activation on fMRI than patients with normal findings or those with incipient myelopathy. In addition, the patterns of cortical motor activation altered significantly at 6 months after spinal cord decompression, which was shown by an increase or decrease in activation of the relevant motor cortex areas.

[Effects of spinal cord decompression in patients with cervical spondylotic myelopathy oncortical brain activations]. / Efekt dekomprese krcní míchy pri spondylogenní myelopatii na korové funkce mozku.

INTRODUCTION: The aim of this project was to compare and evaluate cortical sensorimotor adaptations as measured by brain fMRI (functional magnetic resonance imaging) in patients before and after surgery for cervical spondylotic myelopathy (CSM), i.e., after spinal cord decompression. MATERIAL AND METHODS: Study inclusion required evidence of CSM on MRI of the cervical spine, anterior compression of the spinal cord by osteophytes, or disc herniation. We measured the antero-posterior diameter of the spinal canal stenosis before and 3 months after surgery. Surgery was performed at one or two levels from the anterior approach with implantation of radiolucent spacers, without plate fixation. Each participant underwent two fMRI brain examinations, the first one preoperatively and the second one 6 months following surgery. Subjects performed acoustically paced repetitive wrist flexion and extension of each upper extremity according to block design. MRI data were acquired using 1.5 Tesla scanners. Statistical analysis was carried out using the general linear model implemented in FEAT 6.00 (FMRI Expert Analysis Tool), part of the FSL 5.0 package (FMRIB Software Library). The group differences were evaluated using paired t-test and the resulting statistical maps evaluated as Z-score (standardised value of the t-test) were thresholded at a corrected significance level of p <0.05. The study group consisted of 7 patients including 5 female and 2 male patients, with the average age of 55.7 years. Patients with cervical spondylogenous radiculopathy were evaluated as a control group. RESULTS: The analysis of mean group effects in brain fMRI during flexion and extension of both wrists revealed significant activation in dorsal primary motor cortex contralaterally to the active extremity and in adjacent secondary motor and sensory areas, bilaterally in supplementary motor areas, the anterior cingulum, primary auditory cortex, in the region of the basal ganglia, thalamus and cerebellum. After surgery, the cortical activations and maximum Z-scores decreased in most areas. Analysis of differences between sessions before and after surgery showed a statistically significant activation decrease during movement of both extremities in the right parietal operculum and the posterior temporal lobe. During left wrist movement, there was additional activation decrease in the right superior parietal lobe, the supramarginal gyrus, insular cortex, and the central operculum. In contrast, an activation decrease was detected in the left middle temporal gyrus during right wrist movement. CONCLUSION: An average difference of anteroposterior cervical spinal canal distance before and after surgery of CSM was 2.67 millimetres, representing a 40% increase; the cross-sectional area of the spinal canal increased by 37% and that of the spinal cord by 36%. Functional MRI of the brain revealed significant activation especially in primary and secondary motor cortex and sensory areas in patients with CSM. After surgical decompression of the spinal cord, cortical activations and maximum Z-score decreased in the majority of areas. We proved decreased cortical activation on functional MRI of the brain after surgery in patients with CSM (evaluated according to MRI of cervical spine), even at an initial stage of the disease.

Modality effects in paced serial addition task: differential responses to auditory and visual stimuli.

Paced Auditory Serial-Addition Task (PASAT) is a complex task commonly used to examine patients with diffuse brain damage. A visual version of the neuropsychological test (Paced Visual Serial-Addition Task, PVSAT) has also been introduced to clinical practice, and both versions were adapted to be used in neuroimaging, namely functional magnetic resonance imaging (fMRI). The aim of our work was direct comparison of auditory and visual versions of the paced serial addition test (PASAT/PVSAT) in a within-subject and within-session study and description of the commonalities and differences in both activated and deactivated brain regions. Twenty young adult right-handed healthy volunteers participated in the study and underwent whole-brain fMRI examination during PASAT and PVSAT performance. Higher-level statistical analysis was performed to generate group mean activation and deactivation maps for both tasks, their conjunctions and differences across modalities. In PASAT/PVSAT activation conjunction analysis, we confirmed the existence of a modality-independent neural network similar to working memory tasks and to previous PASAT or PVSAT studies. In PASAT/PVSAT deactivation conjunction analysis, we observed a rather symmetrical extensive pattern of deactivated regions, overlapping the default mode network. Significant differences between PASAT and PVSAT were found in the right frontal eye field (FEF) and bilaterally in the striate and extrastriate cortices. Activation in one task and deactivation in the other jointly contributed to significant differences in all occipital and occipitotemporal regions. Both tasks activated right FEF, but activation during PASAT was significantly stronger than during PVSAT. Between-modality differences should be considered when preparing and interpreting neuroimaging experiments.