Manifest disease and motor cortex reactivity in twins discordant for schizophrenia

Schizophrenia is often associated with difficulties in distinguishing between actions of self and of others. This could reflect dysfunctionof the mirror neuron system which directly matches observedand executed actions. We studied 11 people with schizophreniaand their co-twins without manifest disease, using stimulus-inducedchanges in the magnetoencephalographic $~$ 20 Hz rhythm as an indexof activation in the motor cortex part of the mirror neuronsystem. During action observation and execution, motor cortexreaction was weaker in those with schizophrenia than in theirco-twins, suggesting a disease-related dysfunction of motorcognition.

INTRODUCTION

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INTRODUCTION

During psychotic episodes people with schizophrenia often havedifficulties with awareness of their own actions and recognitionof other individuals’ actions, evident from beliefs ofalien control (Daprati et al, 1997). Such difficulties, likeechopraxia (see e.g. Chapman & McGhie, 1964) and activitydelusions (patients feel that they influence others to act; Stanghellini & Rossi Monti, 1993), could be related todysfunction of the mirror neuron system, which matches executedand observed motor actions (Rizzolatti et al, 1996). The coresystem comprises the inferior frontal gyrus (Broca’sregion in the left hemisphere), the inferior parietal lobule and the primary motor cortex.

Here we tested whether people with schizophrenia would showabnormalities in the motor cortex part of their mirror neuronsystem during observation and execution of finger movements.Earlier studies have indicated abnormal motor cortex functionin patients with schizophrenia compared with healthy participants(reviewed by Spence, 2003). We applied a well-established methodto monitor motor cortex $~$ 20 Hz magnetoencephalographic (MEG)activity (Hari et al, 1998). In response to electrical mediannerve stimuli, this $~$ 20 Hz rhythm is first transiently and bilaterallysuppressed, and then 200–400 ms later is strongly enhanced(Fig. 1a), probably reflecting cortical inhibition (Salmelin & Hari, 1994; Chen et al, 1999). Consequently, the size of the ‘rebound’reflects the functional state of the primary motor cortex;for example the rebound is abolished when the person manipulatesan object (Hari et al, 1998).

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Fig. 1 (a) The level of the $~$ 20 Hz rhythm recorded from the left motor cortex (see inset) in a representative participant after right median nerve stimulation (0 ms). In the ‘rest’ condition the $~$ 20 Hz rhythm is blocked for about 400 ms after which it shows a ‘rebound’ enhancement as a signature of motor cortex stabilisation. In the ‘action’ condition (Act) the motor cortex is active during the participant’s own finger movements and no rebound is observed. In the ‘observation’ condition (Obs) the rebound is of lower amplitude than during rest, indicating partial activation of the motor cortex during action observation. (b) (c) The $~$ 20 Hz reactivity in all participants, quantified as the difference between rest and observation and displayed as a function of the difference between rest and action. In accordance with earlier studies on healthy individuals, nearly all data points are to the right of the diagonal (dashed line), meaning that the suppression of the $~$ 20 Hz rebound is less marked in the observation than the action condition. In most cases (see text for statistics), values for the twin with manifest disease (•) are lower (on both axes) than for the non-affected twin ( ${circ}$ , data for twin pairs connected with lines), indicating lower motor cortex reactivity during both action observation and action execution.

We compared motor cortex reactivity within schizophrenia-discordanttwin pairs, thereby controlling for a portion of the geneticinfluences on brain physiology. Some of the non-affected co-twinsresembled their twin in possessing features of schizotypalpersonality, which further increased the suitability of thiscomparison for pinpointing brain abnormalities related to manifestschizophrenia.

METHOD

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METHOD

Participants were derived from a randomly selected subset of335 schizophrenia-discordant twin pairs, identified (for anotherstudy) in a cohort of all 9562 pairs of same-sex twins bornin Finland between 1940 and 1957 (Cannon et al, 2000). TheStructured Clinical Interview for DSM–III–R AxisI Disorders (patient or non-patient edition; Spitzer et al, 1989) served for verification of the diagnoses in all participants.Interviewers were masked to zygosity and diagnostic status.A diagnosis of schizoaffective disorder, affective type ina twin with manifest disease or a psychotic disorder diagnosisin a non-affected twin led to exclusion of that twin pair (Cannon et al, 2000). Eleven twin pairs (aged 49–64 years, mean age 54.4 years,s.d.=4.8, five monozygotic and six dizygotic) participatedin the study after informed consent and ethics committee approval.All the participants with manifest disease were out-patientsin stable clinical condition (further details in a data supplementto the online version of this report). For all pairs, zygosity was determined by DNA analysis (for details see Cannon et al, 2000).

Neuromagnetic data were acquired during three experimental conditions:(a) rest – the participants rested in a relaxed state;(b) observation – the participants observed the experimenter manipulate a small object with her right-hand fingers; (c)action – the participants manipulated the small objectwith their right-hand fingers without seeing their own hand.

The left and right median nerves were stimulated alternatelyat the wrists (0.2 ms constant current pulses at intensitiesexceeding the motor threshold), once every 1.5 s. Signals from204 planar gradiometers of a helmet-shaped whole-scalp neuromagnetometer(Vectorview, Neuromag, Helsinki, Finland) were analysed. Stimulus-relatedchanges in the level of the $~$ 20 Hz rhythm were quantified byfirst filtering signals through 14–30 Hz, then rectifying them and finally averaging them time-locked to the median nervestimuli (approximately 100 signals averaged per condition).The strength of the rebound in each condition was then quantified(from the MEG channel with the strongest rebound suppressionduring action observation) as the mean level from 300 ms to1300 ms after stimuli (Salmelin & Hari, 1994).

RESULTS

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RESULTS

Figure 1a shows the $~$ 20 Hz motor cortex level for one participant.The rebound, peaking at 700 ms, was abolished during objectmanipulation and significantly suppressed during observation,as shown previously (Schnitzler et al, 1997; Hari et al, 1998). Figure 1b and 1c illustrate the $~$ 20 Hz reactivity in all twinpairs. For both hemispheres and for both observation and actionconditions, the twins with schizophrenia showed weaker reactivityof the $~$ 20 Hz rhythm than their non-affected co-twins (binomial test for n=11 pairs: rest–action P=0.033 and rest–observationNS in left hemisphere; rest–action P=0.006 and rest–observationP=0.006 in right hemisphere).

The rest levels of the $~$ 20 Hz rhythm did not differ between affected and non-affected co-twins, nor was there any statisticallysignificant difference between the groups in the strengthsof cortical responses peaking in the primary somatosensorycortex 20 ms and 35 ms after median nerve stimuli (t-test,P $≥$ 0.2). The $~$ 20 Hz reactivity and the dosages of antipsychoticmedication were not correlated (Pearson’s r=0.43, P=0.19)(further details in a data supplement to the online versionof this report).

DISCUSSION

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DISCUSSION

The $~$ 20 Hz motor cortex rhythm in the twins with schizophreniawas systematically less reactive than in their non-affectedco-twins, both during action observation and execution, withno sign of an additional mirror neuron system abnormality.Since the observed effects were not correlated with medication,we attribute them to the disease itself. The similar somatosensory cortical responses and the comparable resting levels of therhythmic activity in non-affected and affected participantsrender implausible any general dysfunctioning of cortical responsivenessin the patient group. The weakened $~$ 20 Hz reactivity, specificto clinically manifest disease in the affected twins, couldbe related to a deficit in motor cognition affecting both the command and the experience of action, both important for delusionsof control (Frith, 2005). Further studies should test moreextensively the functionality of motor and sensory mirroring in people with schizophrenia, focusing on subgroups displayingspecial abnormalities in the experience of action.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

Supported by the Academy of Finland (National Centers of Excellence Programme 2006–2011), Sigrid Jusélius Foundation,and the National Institute of Mental Health, USA (MH52857).We thank Ulla Mustonen for help in recruiting the participants.

REFERENCES

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