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A study of the spontaneous and evoked spindle activity in schizophrenic and control subjects

Final Report Summary - SPINDLESINSCHIZO (A study of the spontaneous and evoked spindle activity in schizophrenic and control subjects)

Project context and objectives

The objectives of this project were:
-to investigate the spontaneous sleep electroencephalography (EEG) patterns, especially sleep spindles, in patients with schizophrenia and compare them to healthy and psychiatric controls;
-to characterise the neuronal circuitry underlying sleep spindle activity;
-to assess whether these thalamo-cortical circuits had an intrinsic defect in their oscillatory properties in schizophrenia.

Work performed

Sleep spindles are waxing / waning fast (12-16 Hz) oscillations, which are initiated by the thalamic reticular nucleus and modulated/amplified by thalamo-thalamic and thalamo-cortical circuits. This means that the identification of reduced spindle parameters may help to determine deficits in specific thalamo-cortical circuits in schizophrenia. Sleep provides important advantages for investigating possible dysfunctions in brain circuits in schizophrenia, given that sleep recordings minimise waking-related confounding factors, including changes in the level of attention, impaired cognitive ability and the presence of psychotic symptoms. Similarly, using a combination of Transcranial Magnetic Stimulation (TMS) with simultaneous high density (hd)-EEG during wakefulness, it is possible to characterise the intrinsic activity of thalamo-cortical circuits without engaging subjects in cognitive tasks, and thalamo-cortical circuits can be directly examined.

In this project, we took advantage of these recently available approaches (sleep hd-EEG, TMS in combination with hd-EEG during wakefulness) to identify EEG oscillatory deficits in schizophrenia as well as their underlying thalamo-cortical circuits.

To pursue the first objective, we employed a 256-channel high-density (hd) EEG system, which offers both high spatial and temporal resolution. Specifically, in the first part of the project we focused on performing whole-night-sleep hd EEG recordings in patients with schizophrenia as well as in psychiatric and healthy comparison subjects. Also, for EEG analysis purposes, we have been developing automated algorithms for the detection of sleep and slow wave to thoroughly characterise these non-rapid eye movement (NREM) sleep oscillations.

The main results achieved in this first part of the project are presented in a study that was recently published in the American Journal of Psychiatry (Ferrarelli et al., Am J Psychiatry. 2010 Nov;167(11):1339-48). In this study, whole-night high-density EEG recordings were performed in 49 schizophrenia patients, 20 non-schizophrenia patients receiving antipsychotic medications, and 44 healthy subjects. Schizophrenia patients showed a whole-night reduction in both slow (12-14 Hz) and fast (14-16 Hz) spindle amplitude, duration, number and integrated activity (ISA) in the prefrontal, centroparietal and temporal regions. ISA and the spindle number were the most defective parameters, corresponding to a percentage of separation between schizophrenics and control groups close to 90 %. These findings had three important implications:

1. spindle deficits were not found in non-schizophrenic psychiatric patients taking antipsychotics, thus suggesting that such deficits are not due to antipsychotic medications but likely to reflect a dysfunction of specific neuronal circuits;
2. the circuits defective in schizophrenia involve intra-thalamic and thalamo-cortical loops, given the role of these circuits in sleep spindle generation and maintenance;
3. the presence of these deficits in a large group of patients with schizophrenia is consistent with the notion that defective EEG oscillations may represent a biomarker / endophenotype of schizophrenia.

To achieve the second goal of the project, we employed a combination of anatomical and functional measures to further characterise the thalamic and cortical contribution to the sleep spindle deficits in schizophrenia. Specifically, anatomical region-of-interest analysis (i.e. thalamic volumes) and EEG source modelling (i.e. spindle-related cortical currents) were performed in patients with schizophrenia and healthy comparison subjects. Notably, source modelling analysis is a recently available method, which estimates the cortical sources underlying scalp-recorded activity, thus significantly improving the spatial information provided by EEG recordings. We found that schizophrenia patients had reduced mediodorsal (MD) thalamic volumes, especially on the left side, compared to healthy controls, whereas whole thalami and lateral geniculate nuclei did not differ between the two groups (Ferrarelli et al. in preparation). Furthermore, left MD volumes were strongly correlated with the number of scalp-recorded spindles in an anterior frontal region. Finally, cortical currents underlying these anterior frontal spindles were localised in the medial prefrontal cortex, and these currents at the peak of spindle activity were significantly reduced in schizophrenia patients in relation to healthy comparison subjects. Altogether, these findings point to deficits in specific frontal thalamo-cortical circuitry in schizophrenia.

To achieve the final objective of the project, we employed a combination of hd EEG with simultaneous TMS in patients with schizophrenia and healthy comparisons. Specifically, hd EEG recordings during TMS of four cortical areas were performed, and several TMS-evoked EEG oscillation parameters, including synchronisation, amplitude and natural frequency, were compared across the groups. We found that patients with schizophrenia showed a slowing in the natural frequency of the frontal/prefrontal regions compared with healthy control subjects (from an average of a 2-Hz decrease for the motor area to an almost 10-Hz decrease for the prefrontal cortex). Furthermore, the prefrontal natural frequency of individuals with schizophrenia was slower than in any healthy comparison subject and correlated with both Positive and Negative Syndrome Scale scores and reaction time on the Penn Word Recognition Test. These findings were recently published in the Archives of General Psychiatry (Ferrarelli et al., Arch Gen Psychiatry, 2012 Aug; 69(8): 766-774).

Main results

Altogether, these findings suggest that patients with schizophrenia have intrinsic deficits in the activity of frontal cortical / thalamocortical circuits, and that these deficits can be appreciated during sleep as reduced sleep spindle activity as well as during resting wakefulness, by measuring TMS-evoked EEG frontal fast oscillations. Notably, these measures were found to be defective in nearly every patient with schizophrenia compared to non-schizophrenic individuals and were found to correlate with some of the symptoms as well as the cognitive dysfunctions of schizophrenia, thus suggesting that some of these measures may represent a candidate biological marker for this disorder.