Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of First Rank Symptoms (FRS) on Schizophrenia
Condition: Schizophrenia Patients With First Rank Symptoms
MeSH terms: Schizophrenia
Study type: Interventional

Summary: 
      First rank symptoms are core symptoms of schizophrenia. the investigators want to offer an
      integrative approach to better understanding of the mechanisms involved in the first rank
      symptoms and therefore, in schizophrenia, as well as the neuronal modulation mechanisms
      obtained by rTMS. It will be to pass a functional magnetic resonance imaging (fMRI) at rest
      for healthy volunteers, and for patients before and after rTMS modulation, to view brain
      structures activated in the resting state network, and in order to study

        1. the difference of the resting-state network between healthy volunteers and people with
           schizophrenia,

        2. if the response to rTMS boost can be predicted by resting-state network of patients
           before treatment and

        3. if rTMS changes activations in the brain of patients. This will ultimately provide rTMS
           as a treatment of first rank symptoms.
    

Detailed description: 
      Schizophrenia is a common psychiatric disorder that affects approximately 1% of the general
      population. This disease can be described in three dimensions: disorganization, delusions and
      negative signs. The "first rank symptoms" (FRS) were first described by Kurt Schneider. These
      are core symptoms of schizophrenia that were combined to make pathognomonic signs of the
      disease and remain at the center of many classifications of the disease. These symptoms are
      voices or thoughts expressed aloud, voices who argue them, voices that comment on behavior or
      thoughts, delusional perceptions, experiences of body influences, thoughts influences,
      impulses from external influences, the will controlled by external forces, thoughts stolen by
      external forces or others, thoughts interferences by other thoughts, publication thoughts.
      These symptoms reveal difficulty in distinguishing self and other in action, thought or
      physical individual. Thus, the FRS are a gateway to agency disorder, disorder of the sense of
      body ownership and familiarity disorder.

      Agency is the ability to distinguish ones own actions from those of others. The sense of body
      ownership is difficult to distinguish from the sense of agency. It is the knowledge that the
      arm (for example) which make this action is mine. A disorder of sense of body ownership may
      lead to the illusion of a phantom limb and it is very interesting to separate both mechanisms
      of body ownership and agency as wall as the networks involved in agency of those involved in
      the sense of body ownership. Familiarity is the feeling associated with the sight of someone
      close. Thus, in familiarity disorder, patient recognizes the facial features of relatives,
      but feels no sense of familiarity and attributes this to the replacement of the close by an
      impostor. Familiarity disorders can be understood through the 2-ways model of faces of
      processing in which the ventral pathway would be affected in the familiarity disorder. The
      ventral pathway involves a network which extends from the visual cortex to the superior
      temporal sulcus, the inferior parietal lobe and the cingulate gyrus to join the dorsal
      pathway in the hypothalamus.

      In addition, agency studies imply the superior temporal sulcus and the inferior parietal
      lobule as regions involved in distinguishing self / others. Nowadays, remains a difficulty to
      clearly identify the different functions of the regions involved in agency.

      Few neuroimaging studies can identify key areas of the sense of body ownership; in fact,
      protocols are difficult to adapt for use in a scanner. However, there are few studies that
      highlight, as was expected, extrastriatal body area as well as areas that may be involved in
      agency. Experiments have difficulty differentiating, as the investigators said, the sense of
      body ownership from agency, but the investigators have a validated tool, the rubber hand
      illusion, to differentiate sense of body ownership and agency. This tool has already been
      validated in healthy subjects , and was the subject of a study in our unit on patients with
      schizophrenia about to be published. In addition, several studies have shown that the
      performance at the rubber hand illusion task were modified by repeated Transcranial Magnetic
      Stimulation (rTMS) applied to the extrastriatal body area (EBA) or to the inferior parietal
      lobule (IPL) or to the temporo-parietal junction (TPJ).

      Transcranial magnetic stimulation or TMS modulate cortical excitability without serious side
      effects when used at frequencies and intensities recommended in the literature. Low frequency
      rTMS is a recognized for treatment-resistant auditory hallucinations in schizophrenia. This
      is therefore an interesting therapeutic innovation that will benefit to residual symptoms, in
      adjunction to a well conducted medical treatment in schizophrenia.

      To our knowledge, no study has been performed using rTMS as a treatment for FRS in
      schizophrenia. The investigators propose to evaluate the impact of treatment with
      low-frequency rTMS applied to the superior temporal sulcus in its posterior part (pSTS) on
      disorders of agency and familiarity. Indeed, it is well established that low-frequency rTMS
      (1 Hz) of the left TPJ was used to reduce auditory hallucinations in schizophrenia. On the
      same model, the investigators want to offer an innovative and integrative treatment of core
      symptoms of schizophrenia with the specificity of not focusing on a single symptom. The
      choice of pSTS allows also operating on the sense of body ownership inasmuch the TPJ is
      adjacent to the pSTS.

      In addition, in order to have a more comprehensive study incorporating different aspects of
      the pathophysiology of schizophrenia, the investigators want to add a functional magnetic
      resonance imaging (fMRI) of resting-state. This would be to pass a fMRI for healthy
      volunteers. For people with schizophrenia, they will pass a fMRI before and after treatment
      for visualizing brain structures activated in the resting-state network, in order to study

        1. the difference in resting-state circuitry between healthy volunteers and schizophrenia
           patients

        2. whether the response to treatment with rTMS could be predicted by resting-state network
           of patients before treatment and

        3. whether treatment with rTMS could modulate brain activations of patients.

      Indeed, the resting-state network is the brain activity that occurs when a subject leaves his
      mind at rest without any particular task. Self-awareness is involved in this resting-state
      network. This network involves bilateral structures with the main nodes in medial prefrontal
      cortex, posterior cingulate cortex, precuneus and angular gyrus. People with schizophrenia
      exhibit connectivity anomalies in the resting-state network that are temporal connection
      anomalies. In acoustico-verbal hallucinations, people with schizophrenia have a resting-state
      network particularly active in the auditory cortex. Authors have proposed that this
      hyperactivity of the auditory cortex in the resting-state network would make patients more
      vulnerable to attribute external stimuli to them.

      Similarly, it can be postulated that patients with FRS would have a hyperactivity of the
      resting-state network especially in the pSTS and the TPJ, which would lead to a difficulty in
      distinguishing oneself and others and thus, to FRS. Thus, the investigators hypothesize that
      patients with abnormal functional connectivity in the resting-state network (mainly in the
      pSTS and TPJ, which the investigators will then be boost in rTMS) will have a better response
      to treatment and that, after rTMS treatment, a change will be visible on neuronal activation
      of resting-state network in fMRI.
    

Intervention name(s): rTMS treatment; placebo treatment
Intervention type(s): Device; Device
Intervention description(s): patient will be treated with 10 sessions in 5 days with low frequency (1Hz) of Repetitive Transcranial Magnetic Stimulation (rTMS); patient will be treated with 10 sessions in 5 days with low frequency (1Hz) of Sham-controlled
Other intervention name(s): intervention; placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; rTMS; first rank symptoms