We report electroencephalography (EEG) results from a non-patient pilot study conducted whilst developing a neuromodulation approach for improving visual spatial working memory (vSWM) in people with schizophrenia. Working memory impairments are common in people with schizophrenia yet respond poorly to current drug treatments. Transcranial magnetic stimulation (TMS), a minimally-invasive, well-tolerated, brain stimulation technique that is performed whilst a person is awake and alert, may improve working memory performance. However, results have been inconsistent, possibly because TMS was delivered during the heterogenous “resting-state”. We delivered TMS to left dorsolateral prefrontal cortex time-locked to specific events in a vSWM task, aiming to modulate functional networks involved in encoding spatial data into working memory.

Each trial in the vSWM task started with a 2-second-long sample display containing either three or four coloured circles positioned at random locations. This was followed by a 2-second delay period. At the end of the delay period, a visual cue appeared, indicating the target colour. Participants moved a crosshair to the screen location where the target had appeared. We recorded 64-channel EEG throughout. In Experiment 1, twelve participants completed three- and four-item task versions. In Experiment 2, eighteen participants completed the four-item task in three separate blocks within a single session. Between blocks, they completed a short task version alongside TMS. TMS (intermittent theta burst stimulation, 600 pulses, 3.3 minutes) was delivered over the F3 electrode position. Each stimulation on-phase was synchronised to coincide with the onset of sample display. In a random order, one TMS block was active, and one was sham (90° coil rotation).

In Experiment 1, EEG showed decreases (“desynchronisation”) in beta (13–30 Hz) power during sample display and increases (“synchronisation”) during the delay period. Both effects were greater in the four-item condition, and in posterior electrodes. In Experiment 2, posterior beta desynchronisation during sample display was greater following either active or sham stimulation. However, synchronisation during the delay period reduced following sham and increased only following active stimulation. Likewise, performance declined following sham but remained stable or improved following active stimulation.

We examined the effects of TMS on electrophysiological signals evoked during a spatial working memory task. We found that beta-band oscillatory activity, thought to safeguard stored information during memory delays, was increased by memory load and maintained or restored in blocks following active TMS. These effects were greatest over parietal/occipital areas. It is suggested that this beta activity serves to protect memory traces from distractors (in the current case, internal distractors). Notably, if TMS enhances delay activity within areas of the brain involved in stimulus representation that are distal from the stimulation site, then its effects are best understood as network level modulations of brain activity.

The structural integrity of the anterior cingulum has been repeatedly observed to be abnormal in patients with schizophrenia. More recently, aberrant myelination of frontal fasciculi, especially, cingulum has been proposed to underlie delayed corollary discharges that can affect sense of agency and contribute to delusions of control (Schneiderian delusions). Using the magnetization transfer phenomenon at an ultra-high field 7T MRI, we investigated the putative myelin content of cingulum bundle in patients with schizophrenia.

Seventeen clinically stable patients with schizophrenia and 20 controls were recruited for this 7T MRI study. We used a region-of-interest method and extracted magnetization transfer ratio (MTR) from left and right dorsal cingulum bundles and estimated patients v. controls differences. We also related the cingulum MTR values to the severity of Schneiderian delusions.

Patients had a significant reduction in the MTR, indicating reduced myelin content, in the cingulum bundle (right cingulum Hedges’ g = 0.91; left cingulum g = 0.03). The reduced MTR of left cingulum was associated with higher severity of Schneiderian delusions (τ = −0.45, p = 0.026) but no such relationship was seen for the right cingulum MTR (τ = −0.136, p = 0.50) among patients. The association between the left cingulum MTR and Schneiderian delusions was not explained by the presence of other delusions, hallucinations, disorganization or negative symptoms.

Dysmyelination of the cingulum bundle is seen in a subgroup of patients with schizophrenia and may be involved in the mechanism of Schneiderian delusions.

Whether there are distinct subtypes of schizophrenia is an important issue to advance understanding and treatment of schizophrenia.

To understand and treat individuals with schizophrenia, the aim was to advance understanding of differences between individuals, whether there are discrete subtypes, and how fist-episode patients (FEP) may differ from multiple episode patients (MEP).

These issues were analysed in 687 FEP and 1880 MEP with schizophrenia using the Positive and Negative Syndrome Scale for (PANSS) schizophrenia before and after antipsychotic medication for 6 weeks.

The seven Negative Symptoms were correlated with each other and with P2 (conceptual disorganisation), G13 (disturbance of volition), and G7 (motor retardation). The main difference between individuals was in the cluster of seven negative symptoms, which had a continuous unimodal distribution. Medication decreased the PANSS scores for all the symptoms, which were similar in the FEP and MEP groups.

The negative symptoms are a major source of individual differences, and there are potential implications for treatment.

Brain serotonin2 (5-hydroxytryptamine2; 5-HT2) receptors were considered potential targets for therapeutic efficacy of electroconvulsive therapy (ECT), but pre-clinical studies showed that electroconvulsive shock up-regulates 5-HT2 receptors in contrast to antidepressant medications, which down-regulate brain 5-HT2 receptors. Positron emission tomography (PET) studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT2 receptors, but the effects of ECT on these receptors in individuals with depression are unknown.

To determine if a course of ECT alters brain 5-HT2 receptors in individuals with depression and whether such changes correlate with improvement in symptoms.

Fifteen people with major depression, refractory to antidepressant therapy and referred for a course of ECT, had an [18F]setoperone scan during baseline drug-free washout period and another after a course of ECT. We assessed changes in brain 5-HT2 receptors with ECT and their relationship to therapeutic outcome.

Widespread reduction in brain 5-HT2 receptors was observed in all cortical areas with changes slightly more prominent in the right hemisphere. There was a trend for correlation between reduction in brain 5-HT2 receptors in right parahippocampal gyrus, right lingual gyrus and right medial frontal gyrus, and improvement in depressive symptoms.

Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT2 receptors in individuals with depression. The ability of ECT to further down-regulate brain 5-HT2 receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression.

Although 5-hydroxytryptamine (5-HT) has been implicated in mania, the precise alterations in the 5-HT system remain elusive.

To assess brain 5-HT2 receptors in drug-free individuals experiencing a manic episode in comparison with healthy volunteers using positron emission tomography (PET).

Participants (n = 10) with DSM–IV bipolar I disorder – manic episode and healthy controls (n = 10) underwent [18F]- setoperone scans. The differences in 5-HT2 receptor binding potential between the two groups were determined using statistical parametric mapping (SPM) analysis.

Age was a significant correlate with 5-HT2 receptor binding potential with a similar magnitude of correlation in both groups. The SPM analysis with age as a covariate showed that the individuals with current mania had significantly lower 5-HT2 receptor binding potential in frontal, temporal, parietal and occipital cortical regions, with changes more prominent in the right cortical regions compared with controls.

This study suggests that brain 5-HT∗2 receptors are decreased in people with acute mania.

Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought disorder is unknown.

To assess the interrater reliability, sensitivity and factor structure of a new assessment instrument, the Thought and Language Index (TLI), and to determine if minor aberrations detectable in the speech of healthy individuals are related to the more severe formal thought disorders characteristic of schizophrenia.

Interrater reliability was evaluated by determining the intraclass correlation for the ratings by five assessors. Factor analysis of the TLI scores of 87 patients was performed, and TLI scores in matched patients and controls were compared.

The intraclass correlation was good for individual TLI items, and excellent for sub-scale scores. Factor analysis identified three groups of approximately orthogonal disorders. Mild speech aberrations were observed in healthy participants and in patients with schizophrenia. The prevalence of mild aberrations was correlated with the prevalence of definite formal thought disorders.

The TLI is reliable and capable of detecting subtle disorders. Some mild aberrations occurring in the speech of healthy individuals appear to be attenuated forms of the florid disorders characteristic of schizophrenia.

In the rating scales commonly used for assessing response to antipsychotic treatment, individual items embrace symptoms that apparently arise from distinguishable pathophysiological processes and might be expected to respond differently to treatment.

To test the reliability sensitivity to change and factor structure of a new scale for the assessment of the Signs and Symptoms of Psychotic Illness (the SSPI).

Interrater reliability was evaluated by determining the intraclass correlation for the ratings of 63 patients. Sensitivity to change was assessed in a longitudinal study of 33 patients. Factor structure was determined from scores for 155 patients.

The intraclass correlation was satisfactory for all individual items and excellent for the total score. Scores were sensitive to change. A change in Clinical Global Impression of one unit corresponded to an SSPI total score change of 31%. Factor analysis revealed five clusters of symptoms.

The SSPI provides a sensitive and reliable measure of the five major clusters of symptoms that occur commonly in psychotic illness.

The mechanism by which rapid tryptophan depletion (RTD) paradigm induces depressive relapse in recently remitted patients with depression is unknown.

To determine the effects of RTD on brain 5-HT2 receptors using positron emission tomography (PET) and 18F-labelled setoperone.

Ten healthy women underwent two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days.

The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT2 receptor binding in various cortical regions following the RTD session.

When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT2 receptors, these findings suggest that a decrease in 5-HT2 binding following RTD might be an adaptive response that provides protection against depressive symptoms.

Functional imaging studies indicate that delusions and hallucinations in schizophrenia are associated with overactivity of the left hippocampus and ventral striatum. Hippocampal neuronal firing modulates feedback to cortex via cortico–striato–thalamic loops.

To test the hypothesis that recovery from psychosis is associated with decrease in activity in cortico–striato–thalamic circuits, and, furthermore, that reduction in hippocampal activity predicts the degree of alleviation of delusions and hallucinations.

Positron emission tomography (PET) was used to measure the effects of the atypical antipsychotic, risperidone, on glucose metabolism in eight first-episode schizophrenia patients.

A single dose of risperidone produced decreases in metabolism in ventral striatum, thalamus and frontal cortex. The magnitude of decreases in left hippocampus predicted subsequent reduction in delusions and hallucinations. After six weeks' treatment with risperidone, the decreases in frontal metabolism were more extensive.

The mechanism of antipsychotic action of risperidone entails reduction of hippocampal activity together with reduced feedback via cortico–striato–thalamic loops.