<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02242578</url>
  </required_header>
  <id_info>
    <org_study_id>CR-11-149</org_study_id>
    <nct_id>NCT02242578</nct_id>
  </id_info>
  <brief_title>Treating Refractory Schizophrenia With rTMS</brief_title>
  <official_title>Effect of rTMS Over the Medial Cerebellum on Negative Symptoms and Cognitive Dysmetria in Subjects With Treatment Refractory Schizophrenia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seton Healthcare Family</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Abbott Medical Devices</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Texas at Austin</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Seton Healthcare Family</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Symptomatic treatment of the negative symptoms in schizophrenia (such as social withdrawal,&#xD;
      affective flattening, poor motivation, and apathy) with medications and psychotherapy are&#xD;
      almost non-existent, whereas treatment of the positive symptoms (hallucinations and&#xD;
      delusions) has been more effective with psychotropic medications. The proposed research on&#xD;
      human subjects using a non-invasive technology (such as repetitive transcranial magnetic&#xD;
      stimulation [rTMS]) will provide efficacy data for treating negative symptoms.&#xD;
&#xD;
      The hypotheses are that 1) Cerebellar stimulation will cause activation of thalamic and&#xD;
      frontal cortical networks associated with attentional processes as a component of the&#xD;
      &quot;distracted&quot; affect of schizophrenia; 2) Cerebellar stimulation will cause activation of the&#xD;
      reticular activating system (RAS), and this will allow the &quot;mutism&quot;, which is a negative&#xD;
      symptom, to be partially improved.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and Significance&#xD;
&#xD;
      There is increasing evidence from neuropsychological and imaging studies that cerebellar&#xD;
      function is relevant not only to motor coordination, but equally to cognition and behavior&#xD;
      (Rapoport et al., 2000). Selective modulation of cerebello-thalamocortical pathways, in turn,&#xD;
      is believed to provide an additional means of modulating cortical function. Repetitive&#xD;
      transcranial magnetic stimulation (rTMS) can modulate cortical excitability focally in&#xD;
      conscious subjects. Trains with slow frequency (i.e.,1 Hz) are known to suppress cortical&#xD;
      excitability (Chen et al., 1997), whereas facilitation occurs if frequencies higher than 5 Hz&#xD;
      are used (Berardelli et al., 1998). With respect to rTMS of the cerebellum, a major impact on&#xD;
      cognitive function (Oliveri et al., 2007) has been described.&#xD;
&#xD;
      The cerebellum is a very good candidate to be the generator for intracortical inhibition; its&#xD;
      stimulation can modulate the cortical inhibition. Invasive studies by Robert Heath at Tulane&#xD;
      University revealed that the cerebellum is strongly connected to 2 structures at the core of&#xD;
      the proposed abnormal circuitry in schizophrenia, the septal nuclei and the hippocampus (HC).&#xD;
      According to his theory and findings, the septal nuclei are involved in positive mood&#xD;
      regulation, pleasure. The firing of the HC was correlated with negative affect and sadness&#xD;
      (Heath et al, 1980). By stimulating the fastigial nucleus and vermis of the cerebellum, the&#xD;
      septal nuclei were facilitated to fire and the HC was inhibited. The other component of what&#xD;
      Heath referred to as the &quot;aversive system&quot;, the amygdala was also inhibited. This central&#xD;
      role of the cerebellum in this circuit is analogous to its role in &quot;smoothing&quot; the flow of&#xD;
      movements. When considering emotion and cognition, the cerebellum has a smoothing function.&#xD;
      Aside from direct monosynaptic connections between these sites, there is evidence that the&#xD;
      deep cerebellar nuclei are connected to the parietal cortex, temporal cortex, as well as the&#xD;
      cingulate gyrus. These are all areas that have limbic function. The cerebellum is also&#xD;
      directly connected to the midbrain reticular activating system (RAS). This region is&#xD;
      responsible for levels of consciousness and arousal. By potentiating the activation of the&#xD;
      RAS, wthe investigators e can increase the decreased level of arousal, which in many&#xD;
      schizophrenia patients is akin to psychomotor retardation and mutism (catatonic). Midline&#xD;
      deep cerebellar nuclei efferents have been traced to the hypothalamus, central nuclei of the&#xD;
      thalamus, which are also associative (cognitive) and limbic in function. The Locus Ceruleus&#xD;
      and the substantia nigra, in the brain stem are also monosynaptically connected to the&#xD;
      cerebellum.&#xD;
&#xD;
      The cerebellum is connected to thalamus and motor cortex (frontal cortex) through&#xD;
      cerebello-thalamo-cortical pathway. And as stated above it is also connected to a vast array&#xD;
      of limbic structures, making it a good choice to use to modulate abnormal activity in these&#xD;
      structures.&#xD;
&#xD;
      Purkinje cells, the output neurons of cerebellar cortex reduce the excitatory drive from the&#xD;
      deep cerebellar nuclei via the ventrolateral thalamus to inhibitory neurons in the motor&#xD;
      cortex. Activation of Purkinje cells will inhibit the thalamic drive to intracortical&#xD;
      inhibitory neurons, therefore, decrease the intracortical inhibitory interneuron activity and&#xD;
      decrease in SICI and CSP. On the other hand, inhibition of Purkinje cerebellar cells is&#xD;
      expected to have opposite effect and release the thalamus from inhibitory control, increase&#xD;
      the thalamic drive to stimulate the inhibitory interneurons which can be demonstrated by&#xD;
      increase in SICI and CSP Indeed, applying inhibitory rTMS at frequency of 1 Hz resulted in&#xD;
      increase in SICI (Langguth et al., 2008).&#xD;
&#xD;
      The midline deep cerebellar nuclei, those that are anatomically and phylogenetically related&#xD;
      to the vermis, also send collaterals to the reticular activating system (RAS) of the brain&#xD;
      stem. By increasing the excitatory (Glu) drive on the RAS, the subject will experience&#xD;
      increased awareness and connection to their environment.&#xD;
&#xD;
      For decades, the cerebellum has been thought to be predominantly involved in motor&#xD;
      performance and cognitive operations. Recently, however, a growing body of evidence indicates&#xD;
      that the cerebellum is also involved in emotion. The first evidence for cerebellar&#xD;
      involvement in emotion came from the work of Robert G. Heath during the early fifties.&#xD;
      Although his initial work predominantly involved the electrical stimulation of the septum, he&#xD;
      then began research on stimulation of the cerebellum, thinking that it might provide a better&#xD;
      entry to the emotional circuitry of the brain. Several cerebellar pacemaker studies by Heath&#xD;
      did indeed demonstrate positive effects on mood and personality in patients with psychiatric&#xD;
      illness after electrical stimulation of the cerebellum. Moreover, Schmahmann and Sherman&#xD;
      provided clinical support for the role of the cerebellum and particularly the vermis in the&#xD;
      regulation of emotion and mood. Given its modulatory role on emotion, the midline cerebellar&#xD;
      vermis together with the fastigial nucleus and the flocculonodular lobe have been designated&#xD;
      the limbic cerebellum (Schutter and van Honk 2005). Furthermore, additional evidence for the&#xD;
      involvement of the cerebellum in schizophrenia was supported by genetic, structural and&#xD;
      functional imaging data (Sandyk et al., 1991; Nopoulos et al., 1999; Ichimiya et al., 2001;&#xD;
      Varnas et al., 2007) as well as by clinical evidence (Deshmukh et al., 2002; Ho et al., 2004;&#xD;
      Varambally et al., 2006). For example, in an animal model for schizophrenia using prenatal&#xD;
      infection of mice with human influenza virus, the animal developed behavioral changes similar&#xD;
      to those of schizophrenia and was associated with altered expression of cerebellar genes&#xD;
      (Fatemi et al., 2008). Some studies reported smaller bilateral cerebellar volumes as compared&#xD;
      to controls in first episode schizophrenia patients (Bottmer et al., 2005). One of the first&#xD;
      studies to demonstrate the importance of a dysfunctional cerebellar circuitry in&#xD;
      schizophrenia was a positron emission tomography (PET) study (Andreasen et al., 1996). The&#xD;
      authors examined memory performance in schizophrenia patients and correlate it to blood flow&#xD;
      in cerebello-thalamo-cortical pathway. They used two tasks for memory, namely an easy and a&#xD;
      relatively difficult one. While patients with schizophrenia showed normal performance on the&#xD;
      easy practiced memory task they already demonstrated decreased blood flow in the&#xD;
      cerebello-thalamo-cortical pathway. By contrast, in the relatively more difficult memory&#xD;
      task, schizophrenia patients performed worse than healthy controls and displayed&#xD;
      significantly lowered frontal and cerebellar blood flow (Andreasen et al., 1996).&#xD;
&#xD;
      Consistent with the assumed disruption of the cerebellothalamo- cortical pathway in&#xD;
      schizophrenia is evidence from two proton magnetic resonance spectroscopic imaging (HMRS)&#xD;
      studies. Lower levels of N-acetylaspartate (NAA), a marker for neuron density and viability,&#xD;
      were found in the thalamus and cerebellar vermis (Deicken et al., 2001) in patients with&#xD;
      schizophrenia. In keeping with these findings, lower NAA levels in the vermis and cerebellar&#xD;
      cortex have also been found (Ende et al., 2005) as well as in mediodorsal region of the&#xD;
      thalamus (Ende et al., 2001). In addition, poor executive functioning in patients with&#xD;
      schizophrenia was associated with volumetric reductions in the cerebello-thalamo-cortical&#xD;
      network (Rusch et al., 2007). Moreover, a diffusion tensor imaging (DTI) study has shown that&#xD;
      patients with schizophrenia demonstrate abnormality in the connectivity between cerebellum&#xD;
      and thalamus with possible difference between the right and left cerebellum (Magnota et al.,&#xD;
      2008). Investigating connectivity between the cerebellum and thalamus in schizophrenia using&#xD;
      diffusion tensor tractography: A pilot study). Another DTI study found neuronal&#xD;
      disorganization in the superior peduncle with neuronal disorganization being associated with&#xD;
      poor cognitive performance (Okugawa et al., 2006). Finally, the activity of right and left&#xD;
      cerebellum may not be the same. For example, impaired working memory in schizophrenia is&#xD;
      associated with over and under-activation along the cerebellothalamo- cortical pathway with&#xD;
      under-activation of the left DLPFC and right cerebellum and over-activation of the left&#xD;
      cerebellum (Mendrek et al., 2005).&#xD;
&#xD;
      To date, cerebellar involvement in schizophrenia remains a subject of ongoing study. It was&#xD;
      shown that motor impairments in schizophrenia are related to cerebellar malfunction. Several&#xD;
      studies report that the cerebellum is indeed involved in cognitive (Eyler et al., 2004; Aasen&#xD;
      et al., 2005; Kiehl et al., 2005) and affective (Paradiso et al., 2003; Takahashi et al.,&#xD;
      2004; Stip et al., 2005) impairments. This study aims to clarify the role of the cerebellum&#xD;
      in development of negative symptoms through its regulation of cortical inhibition, activation&#xD;
      of the septal region with reciprocal inactivation of the hippocampus, and RAS activation.&#xD;
&#xD;
      Experimental Design and Methods/Procedures&#xD;
&#xD;
        1. rTMS over the vermis of the cerebellum&#xD;
&#xD;
        2. 5 sessions/week for 1 week&#xD;
&#xD;
        3. Randomization as explained below.&#xD;
&#xD;
      Patients will be randomly assigned to either the high frequency or low frequency Medial&#xD;
      Cerebellum Target Treatment protocol. Each group will then be entered into a randomized,&#xD;
      double-blind, sham-controlled, parallel-design clinical trial that consists of three main&#xD;
      phases: (1) Baseline Psychiatric and Psychometric Testing Exam; (2) 5 rTMS treatments,&#xD;
      double-blind, in 5 treatment sessions/week with active or sham rTMS for over a period of 1&#xD;
      week; and (3) a follow-up period of 3 weeks. The patients will then be reassigned to the&#xD;
      other Frequency (either high or low) Arm of the study. The protocol will then be repeated.&#xD;
      Patients and the investigators, except the investigator who applied rTMS, will be blinded to&#xD;
      the treatment arm.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    IRB approval expired and study ceased.&#xD;
  </why_stopped>
  <start_date type="Actual">January 24, 2011</start_date>
  <completion_date type="Actual">June 11, 2018</completion_date>
  <primary_completion_date type="Actual">June 11, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Scores at 1 Week</measure>
    <time_frame>Participants will be followed for an expected average of 5 weeks</time_frame>
    <description>Participants will receive baseline and post-treatment protocol neuropsychiatric measures. These rating scales are accepted and standardized.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Electroencephalographic (EEG) Measures at 1 Week</measure>
    <time_frame>Participants will be followed for an expected average of 5 weeks</time_frame>
    <description>Electroencephalographic (EEG) recordings and evaluations:&#xD;
Patients will undergo 19-channel EEG recordings before, and immediately after the end of the 5-day rTMS treatment. Patients will be kept awake during this procedure to control for the effects of sleep on EEG. Each EEG recording will be performed by employing scalp electrodes placed according to the International 10-20 system. Data will be analyzed for changes in the spectral characteristics of the EEG, most importantly in delta and beta frequency bands.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Schizophrenia</condition>
  <arm_group>
    <arm_group_label>Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Active rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Sham rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>1 Hz rTMS</intervention_name>
    <description>About 1,000 stimulation pulses over 20 min</description>
    <arm_group_label>Active</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>10 Hz rTMS</intervention_name>
    <description>About 1,000 stimulation pulses over 20 min</description>
    <arm_group_label>Active</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients enrolling to the study:&#xD;
&#xD;
               -  must be stable on their medications at the start of their enrollment in the study&#xD;
                  and throughout the duration of the study;&#xD;
&#xD;
               -  must have no history of substance use of substance-dependence issues over at&#xD;
                  least the past six months;&#xD;
&#xD;
               -  must be able to and have the capacity to provide consent;&#xD;
&#xD;
               -  and if older patient, he/she must be able to participate without a safeguard to&#xD;
                  be present.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients excluded from the study are:&#xD;
&#xD;
               -  Patients with typical clinical considerations that exclude them from treatment&#xD;
                  with TMS (i.e., patients who have had head injuries, patients with metal&#xD;
                  implants, patients with a history of seizures, patients with elevated risk of&#xD;
                  seizures, patients who are taking medications that may interfere with TMS or&#xD;
                  potentiate the related side effects, etc.).&#xD;
&#xD;
               -  Patients who have had changes in their medications (i.e., patients must be stable&#xD;
                  on their medications throughout their participation in the study).&#xD;
&#xD;
               -  Patients with history of substance abuse or substance-dependence anytime over the&#xD;
                  past six months.&#xD;
&#xD;
               -  Patients who are unable (i.e., do not have the capacity) to consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robert Buchanan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Seton Family Hopsitals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Seton Brain and Spine Institute &quot;Brain Stimulation Laboratory&quot;</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Andreasen NC, O'Leary DS, Cizadlo T, Arndt S, Rezai K, Ponto LL, Watkins GL, Hichwa RD. Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9985-90. doi: 10.1073/pnas.93.18.9985.</citation>
    <PMID>8790444</PMID>
  </reference>
  <reference>
    <citation>Ende G, Hubrich P, Walter S, Weber-Fahr W, Kammerer N, Braus DF, Henn FA. Further evidence for altered cerebellar neuronal integrity in schizophrenia. Am J Psychiatry. 2005 Apr;162(4):790-2. doi: 10.1176/appi.ajp.162.4.790.</citation>
    <PMID>15800155</PMID>
  </reference>
  <reference>
    <citation>Ho BC, Mola C, Andreasen NC. Cerebellar dysfunction in neuroleptic naive schizophrenia patients: clinical, cognitive, and neuroanatomic correlates of cerebellar neurologic signs. Biol Psychiatry. 2004 Jun 15;55(12):1146-53. doi: 10.1016/j.biopsych.2004.02.020.</citation>
    <PMID>15184033</PMID>
  </reference>
  <reference>
    <citation>Nopoulos PC, Ceilley JW, Gailis EA, Andreasen NC. An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept. Biol Psychiatry. 1999 Sep 1;46(5):703-11. doi: 10.1016/s0006-3223(99)00093-1.</citation>
    <PMID>10472423</PMID>
  </reference>
  <reference>
    <citation>Picard H, Amado I, Mouchet-Mages S, Olie JP, Krebs MO. The role of the cerebellum in schizophrenia: an update of clinical, cognitive, and functional evidences. Schizophr Bull. 2008 Jan;34(1):155-72. doi: 10.1093/schbul/sbm049. Epub 2007 Jun 11.</citation>
    <PMID>17562694</PMID>
  </reference>
  <reference>
    <citation>Rusch N, Spoletini I, Wilke M, Bria P, Di Paola M, Di Iulio F, Martinotti G, Caltagirone C, Spalletta G. Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia. Schizophr Res. 2007 Jul;93(1-3):79-89. doi: 10.1016/j.schres.2007.01.029. Epub 2007 Mar 26.</citation>
    <PMID>17383859</PMID>
  </reference>
  <reference>
    <citation>Rapoport M, van Reekum R, Mayberg H. The role of the cerebellum in cognition and behavior: a selective review. J Neuropsychiatry Clin Neurosci. 2000 Spring;12(2):193-8. doi: 10.1176/jnp.12.2.193.</citation>
    <PMID>11001597</PMID>
  </reference>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>September 12, 2014</study_first_submitted>
  <study_first_submitted_qc>September 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 17, 2014</study_first_posted>
  <results_first_submitted>March 16, 2021</results_first_submitted>
  <results_first_submitted_qc>March 16, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">April 12, 2021</results_first_posted>
  <last_update_submitted>March 16, 2021</last_update_submitted>
  <last_update_submitted_qc>March 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Seton Healthcare Family</investigator_affiliation>
    <investigator_full_name>Robert J. Buchanan</investigator_full_name>
    <investigator_title>Chief of Functional and Restorative Neurosurgery and Neurosciences</investigator_title>
  </responsible_party>
  <keyword>Negative symptoms</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Schizophrenia</mesh_term>
    <mesh_term>Schizophrenia, Treatment-Resistant</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 23, 2013</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/78/NCT02242578/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Active</title>
          <description>Active rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Sham rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Study terminated and no data collected.</population>
      <group_list>
        <group group_id="B1">
          <title>Active</title>
          <description>Active rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Sham rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="0"/>
            <count group_id="B2" value="0"/>
            <count group_id="B3" value="0"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                </category>
                <category>
                  <title>Male</title>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                </category>
                <category>
                  <title>Asian</title>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                </category>
                <category>
                  <title>Black or African American</title>
                </category>
                <category>
                  <title>White</title>
                </category>
                <category>
                  <title>More than one race</title>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <class_list>
            <class>
              <title>United States</title>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Scores at 1 Week</title>
        <description>Participants will receive baseline and post-treatment protocol neuropsychiatric measures. These rating scales are accepted and standardized.</description>
        <time_frame>Participants will be followed for an expected average of 5 weeks</time_frame>
        <population>Study was terminated (that is, stopped prematurely) and no data were collected for one or more Outcome Measures.</population>
        <group_list>
          <group group_id="O1">
            <title>Active</title>
            <description>Active rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Sham rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Scores at 1 Week</title>
          <description>Participants will receive baseline and post-treatment protocol neuropsychiatric measures. These rating scales are accepted and standardized.</description>
          <population>Study was terminated (that is, stopped prematurely) and no data were collected for one or more Outcome Measures.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Electroencephalographic (EEG) Measures at 1 Week</title>
        <description>Electroencephalographic (EEG) recordings and evaluations:&#xD;
Patients will undergo 19-channel EEG recordings before, and immediately after the end of the 5-day rTMS treatment. Patients will be kept awake during this procedure to control for the effects of sleep on EEG. Each EEG recording will be performed by employing scalp electrodes placed according to the International 10-20 system. Data will be analyzed for changes in the spectral characteristics of the EEG, most importantly in delta and beta frequency bands.</description>
        <time_frame>Participants will be followed for an expected average of 5 weeks</time_frame>
        <population>Study was terminated (that is, stopped prematurely) and no data were collected for one or more Outcome Measures.</population>
        <group_list>
          <group group_id="O1">
            <title>Active</title>
            <description>Active rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Sham rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Electroencephalographic (EEG) Measures at 1 Week</title>
          <description>Electroencephalographic (EEG) recordings and evaluations:&#xD;
Patients will undergo 19-channel EEG recordings before, and immediately after the end of the 5-day rTMS treatment. Patients will be kept awake during this procedure to control for the effects of sleep on EEG. Each EEG recording will be performed by employing scalp electrodes placed according to the International 10-20 system. Data will be analyzed for changes in the spectral characteristics of the EEG, most importantly in delta and beta frequency bands.</description>
          <population>Study was terminated (that is, stopped prematurely) and no data were collected for one or more Outcome Measures.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>0 year</time_frame>
      <desc>Study terminated, no data collected.</desc>
      <group_list>
        <group group_id="E1">
          <title>Active</title>
          <description>Active rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Sham rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)&#xD;
1 Hz rTMS: About 1,000 stimulation pulses over 20 min&#xD;
10 Hz rTMS: About 1,000 stimulation pulses over 20 min</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Study was terminated and no data was collected.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Robert J Buchanan, MD</name_or_title>
      <organization>The University of Texas at Austin</organization>
      <phone>512-324-7991</phone>
      <email>robertbuchanan@utexas.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02242578
org study id: CR-11-149
nct id: NCT02242578
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Symptomatic treatment of the negative symptoms in schizophrenia (such as social withdrawal,
      affective flattening, poor motivation, and apathy) with medications and psychotherapy are
      almost non-existent, whereas treatment of the positive symptoms (hallucinations and
      delusions) has been more effective with psychotropic medications. The proposed research on
      human subjects using a non-invasive technology (such as repetitive transcranial magnetic
      stimulation [rTMS]) will provide efficacy data for treating negative symptoms.

      The hypotheses are that 1) Cerebellar stimulation will cause activation of thalamic and
      frontal cortical networks associated with attentional processes as a component of the
      "distracted" affect of schizophrenia; 2) Cerebellar stimulation will cause activation of the
      reticular activating system (RAS), and this will allow the "mutism", which is a negative
      symptom, to be partially improved.
Background and Significance

      There is increasing evidence from neuropsychological and imaging studies that cerebellar
      function is relevant not only to motor coordination, but equally to cognition and behavior
      (Rapoport et al., 2000). Selective modulation of cerebello-thalamocortical pathways, in turn,
      is believed to provide an additional means of modulating cortical function. Repetitive
      transcranial magnetic stimulation (rTMS) can modulate cortical excitability focally in
      conscious subjects. Trains with slow frequency (i.e.,1 Hz) are known to suppress cortical
      excitability (Chen et al., 1997), whereas facilitation occurs if frequencies higher than 5 Hz
      are used (Berardelli et al., 1998). With respect to rTMS of the cerebellum, a major impact on
      cognitive function (Oliveri et al., 2007) has been described.

      The cerebellum is a very good candidate to be the generator for intracortical inhibition; its
      stimulation can modulate the cortical inhibition. Invasive studies by Robert Heath at Tulane
      University revealed that the cerebellum is strongly connected to 2 structures at the core of
      the proposed abnormal circuitry in schizophrenia, the septal nuclei and the hippocampus (HC).
      According to his theory and findings, the septal nuclei are involved in positive mood
      regulation, pleasure. The firing of the HC was correlated with negative affect and sadness
      (Heath et al, 1980). By stimulating the fastigial nucleus and vermis of the cerebellum, the
      septal nuclei were facilitated to fire and the HC was inhibited. The other component of what
      Heath referred to as the "aversive system", the amygdala was also inhibited. This central
      role of the cerebellum in this circuit is analogous to its role in "smoothing" the flow of
      movements. When considering emotion and cognition, the cerebellum has a smoothing function.
      Aside from direct monosynaptic connections between these sites, there is evidence that the
      deep cerebellar nuclei are connected to the parietal cortex, temporal cortex, as well as the
      cingulate gyrus. These are all areas that have limbic function. The cerebellum is also
      directly connected to the midbrain reticular activating system (RAS). This region is
      responsible for levels of consciousness and arousal. By potentiating the activation of the
      RAS, wthe investigators e can increase the decreased level of arousal, which in many
      schizophrenia patients is akin to psychomotor retardation and mutism (catatonic). Midline
      deep cerebellar nuclei efferents have been traced to the hypothalamus, central nuclei of the
      thalamus, which are also associative (cognitive) and limbic in function. The Locus Ceruleus
      and the substantia nigra, in the brain stem are also monosynaptically connected to the
      cerebellum.

      The cerebellum is connected to thalamus and motor cortex (frontal cortex) through
      cerebello-thalamo-cortical pathway. And as stated above it is also connected to a vast array
      of limbic structures, making it a good choice to use to modulate abnormal activity in these
      structures.

      Purkinje cells, the output neurons of cerebellar cortex reduce the excitatory drive from the
      deep cerebellar nuclei via the ventrolateral thalamus to inhibitory neurons in the motor
      cortex. Activation of Purkinje cells will inhibit the thalamic drive to intracortical
      inhibitory neurons, therefore, decrease the intracortical inhibitory interneuron activity and
      decrease in SICI and CSP. On the other hand, inhibition of Purkinje cerebellar cells is
      expected to have opposite effect and release the thalamus from inhibitory control, increase
      the thalamic drive to stimulate the inhibitory interneurons which can be demonstrated by
      increase in SICI and CSP Indeed, applying inhibitory rTMS at frequency of 1 Hz resulted in
      increase in SICI (Langguth et al., 2008).

      The midline deep cerebellar nuclei, those that are anatomically and phylogenetically related
      to the vermis, also send collaterals to the reticular activating system (RAS) of the brain
      stem. By increasing the excitatory (Glu) drive on the RAS, the subject will experience
      increased awareness and connection to their environment.

      For decades, the cerebellum has been thought to be predominantly involved in motor
      performance and cognitive operations. Recently, however, a growing body of evidence indicates
      that the cerebellum is also involved in emotion. The first evidence for cerebellar
      involvement in emotion came from the work of Robert G. Heath during the early fifties.
      Although his initial work predominantly involved the electrical stimulation of the septum, he
      then began research on stimulation of the cerebellum, thinking that it might provide a better
      entry to the emotional circuitry of the brain. Several cerebellar pacemaker studies by Heath
      did indeed demonstrate positive effects on mood and personality in patients with psychiatric
      illness after electrical stimulation of the cerebellum. Moreover, Schmahmann and Sherman
      provided clinical support for the role of the cerebellum and particularly the vermis in the
      regulation of emotion and mood. Given its modulatory role on emotion, the midline cerebellar
      vermis together with the fastigial nucleus and the flocculonodular lobe have been designated
      the limbic cerebellum (Schutter and van Honk 2005). Furthermore, additional evidence for the
      involvement of the cerebellum in schizophrenia was supported by genetic, structural and
      functional imaging data (Sandyk et al., 1991; Nopoulos et al., 1999; Ichimiya et al., 2001;
      Varnas et al., 2007) as well as by clinical evidence (Deshmukh et al., 2002; Ho et al., 2004;
      Varambally et al., 2006). For example, in an animal model for schizophrenia using prenatal
      infection of mice with human influenza virus, the animal developed behavioral changes similar
      to those of schizophrenia and was associated with altered expression of cerebellar genes
      (Fatemi et al., 2008). Some studies reported smaller bilateral cerebellar volumes as compared
      to controls in first episode schizophrenia patients (Bottmer et al., 2005). One of the first
      studies to demonstrate the importance of a dysfunctional cerebellar circuitry in
      schizophrenia was a positron emission tomography (PET) study (Andreasen et al., 1996). The
      authors examined memory performance in schizophrenia patients and correlate it to blood flow
      in cerebello-thalamo-cortical pathway. They used two tasks for memory, namely an easy and a
      relatively difficult one. While patients with schizophrenia showed normal performance on the
      easy practiced memory task they already demonstrated decreased blood flow in the
      cerebello-thalamo-cortical pathway. By contrast, in the relatively more difficult memory
      task, schizophrenia patients performed worse than healthy controls and displayed
      significantly lowered frontal and cerebellar blood flow (Andreasen et al., 1996).

      Consistent with the assumed disruption of the cerebellothalamo- cortical pathway in
      schizophrenia is evidence from two proton magnetic resonance spectroscopic imaging (HMRS)
      studies. Lower levels of N-acetylaspartate (NAA), a marker for neuron density and viability,
      were found in the thalamus and cerebellar vermis (Deicken et al., 2001) in patients with
      schizophrenia. In keeping with these findings, lower NAA levels in the vermis and cerebellar
      cortex have also been found (Ende et al., 2005) as well as in mediodorsal region of the
      thalamus (Ende et al., 2001). In addition, poor executive functioning in patients with
      schizophrenia was associated with volumetric reductions in the cerebello-thalamo-cortical
      network (Rusch et al., 2007). Moreover, a diffusion tensor imaging (DTI) study has shown that
      patients with schizophrenia demonstrate abnormality in the connectivity between cerebellum
      and thalamus with possible difference between the right and left cerebellum (Magnota et al.,
      2008). Investigating connectivity between the cerebellum and thalamus in schizophrenia using
      diffusion tensor tractography: A pilot study). Another DTI study found neuronal
      disorganization in the superior peduncle with neuronal disorganization being associated with
      poor cognitive performance (Okugawa et al., 2006). Finally, the activity of right and left
      cerebellum may not be the same. For example, impaired working memory in schizophrenia is
      associated with over and under-activation along the cerebellothalamo- cortical pathway with
      under-activation of the left DLPFC and right cerebellum and over-activation of the left
      cerebellum (Mendrek et al., 2005).

      To date, cerebellar involvement in schizophrenia remains a subject of ongoing study. It was
      shown that motor impairments in schizophrenia are related to cerebellar malfunction. Several
      studies report that the cerebellum is indeed involved in cognitive (Eyler et al., 2004; Aasen
      et al., 2005; Kiehl et al., 2005) and affective (Paradiso et al., 2003; Takahashi et al.,
      2004; Stip et al., 2005) impairments. This study aims to clarify the role of the cerebellum
      in development of negative symptoms through its regulation of cortical inhibition, activation
      of the septal region with reciprocal inactivation of the hippocampus, and RAS activation.

      Experimental Design and Methods/Procedures

        1. rTMS over the vermis of the cerebellum

        2. 5 sessions/week for 1 week

        3. Randomization as explained below.

      Patients will be randomly assigned to either the high frequency or low frequency Medial
      Cerebellum Target Treatment protocol. Each group will then be entered into a randomized,
      double-blind, sham-controlled, parallel-design clinical trial that consists of three main
      phases: (1) Baseline Psychiatric and Psychometric Testing Exam; (2) 5 rTMS treatments,
      double-blind, in 5 treatment sessions/week with active or sham rTMS for over a period of 1
      week; and (3) a follow-up period of 3 weeks. The patients will then be reassigned to the
      other Frequency (either high or low) Arm of the study. The protocol will then be repeated.
      Patients and the investigators, except the investigator who applied rTMS, will be blinded to
      the treatment arm.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Scores at 1 Week
time frame: Participants will be followed for an expected average of 5 weeks
description: Participants will receive baseline and post-treatment protocol neuropsychiatric measures. These rating scales are accepted and standardized.
measure: Change From Baseline in Electroencephalographic (EEG) Measures at 1 Week
time frame: Participants will be followed for an expected average of 5 weeks
description: Electroencephalographic (EEG) recordings and evaluations:
Patients will undergo 19-channel EEG recordings before, and immediately after the end of the 5-day rTMS treatment. Patients will be kept awake during this procedure to control for the effects of sleep on EEG. Each EEG recording will be performed by employing scalp electrodes placed according to the International 10-20 system. Data will be analyzed for changes in the spectral characteristics of the EEG, most importantly in delta and beta frequency bands.
arm group label: Active
arm group type: Experimental
description: Active rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)
arm group label: Placebo
arm group type: Experimental
description: Sham rTMS stimulation (1 Hz rTMS, 10 Hz rTMS)
intervention type: Device
intervention name: 1 Hz rTMS
description: About 1,000 stimulation pulses over 20 min
arm group label: Active
arm group label: Placebo
intervention type: Device
intervention name: 10 Hz rTMS
description: About 1,000 stimulation pulses over 20 min
arm group label: Active
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Robert Buchanan, MD
role: Principal Investigator
affiliation: Seton Family Hopsitals
facility: 
country: United States
citation: Andreasen NC, O'Leary DS, Cizadlo T, Arndt S, Rezai K, Ponto LL, Watkins GL, Hichwa RD. Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9985-90. doi: 10.1073/pnas.93.18.9985.
PMID: 8790444
citation: Ende G, Hubrich P, Walter S, Weber-Fahr W, Kammerer N, Braus DF, Henn FA. Further evidence for altered cerebellar neuronal integrity in schizophrenia. Am J Psychiatry. 2005 Apr;162(4):790-2. doi: 10.1176/appi.ajp.162.4.790.
PMID: 15800155
citation: Ho BC, Mola C, Andreasen NC. Cerebellar dysfunction in neuroleptic naive schizophrenia patients: clinical, cognitive, and neuroanatomic correlates of cerebellar neurologic signs. Biol Psychiatry. 2004 Jun 15;55(12):1146-53. doi: 10.1016/j.biopsych.2004.02.020.
PMID: 15184033
citation: Nopoulos PC, Ceilley JW, Gailis EA, Andreasen NC. An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept. Biol Psychiatry. 1999 Sep 1;46(5):703-11. doi: 10.1016/s0006-3223(99)00093-1.
PMID: 10472423
citation: Picard H, Amado I, Mouchet-Mages S, Olie JP, Krebs MO. The role of the cerebellum in schizophrenia: an update of clinical, cognitive, and functional evidences. Schizophr Bull. 2008 Jan;34(1):155-72. doi: 10.1093/schbul/sbm049. Epub 2007 Jun 11.
PMID: 17562694
citation: Rusch N, Spoletini I, Wilke M, Bria P, Di Paola M, Di Iulio F, Martinotti G, Caltagirone C, Spalletta G. Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia. Schizophr Res. 2007 Jul;93(1-3):79-89. doi: 10.1016/j.schres.2007.01.029. Epub 2007 Mar 26.
PMID: 17383859
citation: Rapoport M, van Reekum R, Mayberg H. The role of the cerebellum in cognition and behavior: a selective review. J Neuropsychiatry Clin Neurosci. 2000 Spring;12(2):193-8. doi: 10.1176/jnp.12.2.193.
PMID: 11001597
responsible party type: Principal Investigator
investigator affiliation: Seton Healthcare Family
investigator full name: Robert J. Buchanan
investigator title: Chief of Functional and Restorative Neurosurgery and Neurosciences
mesh term: Schizophrenia
mesh term: Schizophrenia, Treatment-Resistant
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Study was terminated and no data was collected.
point of contact: 