<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/NCT03835468</url>
  </required_header>
  <id_info>
    <org_study_id>PrebioticExtensionStudyGU2</org_study_id>
    <nct_id>NCT03835468</nct_id>
  </id_info>
  <brief_title>The Role of the Microbiota-gut-brain Axis in Brain Development and Mental Health</brief_title>
  <official_title>The Role of the Microbiota-gut-brain Axis in Brain Development and Mental Health</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Surrey</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>FrieslandCampina</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Surrey</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The role of the microbiota-gut-brain axis in brain development and mental health&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Anxiety disorders are debilitating conditions that carry enormous individual, social and&#xD;
      economic costs. For example, it has been estimated that lifelong persistent mental health&#xD;
      problems cost the UK taxpayer £8.6 billion annually. Many mental health problems have their&#xD;
      onset in the transitional period from adolescence to early adulthood, possibly a result of&#xD;
      the complex and concurrent hormonal, genetic, brain maturational and social changes during&#xD;
      this period. Research has shown that brain development and maturation extends well into the&#xD;
      third decade of life and that brain activation patterns in late adolescence and early&#xD;
      adulthood still differ significantly from mature adults. In the recent years, the microbiome&#xD;
      has emerged as a new and important factor that may increase the mental health risk for an&#xD;
      individual. The intestine and the brain are intimately connected via the gut-brain axis,&#xD;
      which involves bidirectional communication via neural, endocrine and immune pathways.&#xD;
      Research in both the human and animal models has also highlighted the important role that&#xD;
      intestinal microbiota play in regulating the brain, subsequent behaviour, and particularly in&#xD;
      anxiety-like behaviour. Most importantly, it has been shown that the period of adolescence&#xD;
      may be a critical window during development where microbiota help fine-tune the gut-brain&#xD;
      axis related to stress responses and anxiety.&#xD;
&#xD;
      The research proposed here will investigate the role of the microbiota-gut-brain axis in&#xD;
      brain development and mental health. Specifically, the researchers will investigate the&#xD;
      effect of prebiotic intake on mental health and well-being in late adolescence/early&#xD;
      adulthood, with a particular focus on cortical excitability and connectivity in the emotion&#xD;
      regulation brain network.&#xD;
&#xD;
      This research will extend previous research into gut-brain interactions into the final years&#xD;
      of adolescence. The period of adolescence is not only important with regards to fine-tuning&#xD;
      emotion regulation networks, but also, as has been shown in recent work, critical for&#xD;
      establishing healthy gut-brain communication patterns. Specifically, here we will investigate&#xD;
      how prebiotic intake (Galacto-oligosaccharides) for 4 weeks affects cognitive functioning,&#xD;
      psychological well-being and the underlying brain networks in a sample of 120 female&#xD;
      undergraduate students (aged 18-25 years). Specifically, the proposed research has two main&#xD;
      aims:&#xD;
&#xD;
        1. To investigate how prebiotic intake affects cortical excitability and plasticity, such&#xD;
           as inhibitory GABA/ excitatory glutamate levels in key emotion regulation brain&#xD;
           networks.&#xD;
&#xD;
        2. To investigate how prebiotic intake affects psychological functioning and well-being, in&#xD;
           particular with regards to anxiety and thought control abilities.&#xD;
&#xD;
      120 participants will be divided into two group of 60 participants, groups will be matched&#xD;
      for age, handedness and socio-economic status. At each testing time (Time 1, 2 and 3),&#xD;
      participants in both groups will undergo comprehensive behavioural and psychological testing&#xD;
      to establish baseline measures of cognitive functioning and psychological well-being (such as&#xD;
      anxiety levels).&#xD;
&#xD;
      Each participant will also be asked to collect a stool sample at home for 16s rRNA sequencing&#xD;
      of the microbiome at both testing times. Group 1 will receive a daily dosage of GOS over 4&#xD;
      weeks, whereas group 2 will receive a placebo over the same period. In addition, participants&#xD;
      from either group will also participate in a brain imaging session to assess the effect of&#xD;
      prebiotic supplement intake on the functional responsiveness of emotion regulation brain&#xD;
      networks.&#xD;
&#xD;
      For this study, The researchers predict that the intervention group will show improvements in&#xD;
      behavioural and psychological variables related to emotion regulation and anxiety in&#xD;
      comparison to the placebo group (Hypothesis 1). Predictions also expect to observe decreased&#xD;
      excitability in core emotion regulation brain regions such as the amygdala and prefrontal&#xD;
      cortex, as assessed via 1H-magnet resonance spectroscopy (Hypothesis 2).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 1, 2019</start_date>
  <completion_date type="Anticipated">March 2023</completion_date>
  <primary_completion_date type="Anticipated">March 2022</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>
    <intervention_model_description>Participants will be randomly assigned into two groups. Group 1 will receive a daily dosage of GOS over 4 weeks, whereas group 2 will receive a placebo over the same period.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in brain indices of emotion regulation abilities as a function of prebiotic intake 1</measure>
    <time_frame>4 weeks of intervention</time_frame>
    <description>Increase in brain-based metabolite concentrations (gamma-aminobutyric acid (GABA)) as assessed via Magnetic resonance spectroscopy in the prebiotics group in comparison to the placebo group.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in brain indices of emotion regulation abilities as a function of prebiotic intake 2</measure>
    <time_frame>4 weeks of intervention</time_frame>
    <description>Increase in functional connectivity in brain networks supporting emotion regulation abilities (as assessed via functional magnetic resonance imaging) in the prebiotics group in comparison to the placebo group.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in psychological measures of emotion regulation abilities as a function of prebiotic intake 1</measure>
    <time_frame>4 weeks of intervention</time_frame>
    <description>Decrease in Trait anxiety (State-Trait Anxiety Inventory, Spielberger, 1977) in the prebiotics group in comparison to the placebo group.. For this inventory, a lower overall score is the desired outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in psychological measures of emotion regulation abilities as a function of prebiotic intake 2</measure>
    <time_frame>4 weeks of intervention</time_frame>
    <description>Decrease in Social Anxiety for adolescents (Social Anxiety Scales, La Greca, 1999) in the prebiotics group in comparison to the placebo group. For this scale, a lower overall score is the desired outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in psychological measures of emotion regulation abilities as a function of prebiotic intake 3</measure>
    <time_frame>4 weeks of intervention</time_frame>
    <description>Increase in thought control ability (Thought control ability questionnaire, Luciano et al., 2005) in the prebiotics group in comparison to the placebo group.. For this questionnaire, a higher overall score is the desired outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in gut microbiome composition as a function of prebiotic intake</measure>
    <time_frame>4 weeks of intervention</time_frame>
    <description>Increase in beneficial gut bacteria (percentage) in the prebiotics group in comparison to the placebo group. Based on stool sample analyses and microbiome sequencing.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in gut microbiome composition as a function of prebiotic intake</measure>
    <time_frame>4 weeks of intervention</time_frame>
    <description>Increase in diversity of gut bacteria in the prebiotics group (number of different bacteria) in comparison to the placebo group. Based on stool sample analyses and microbiome sequencing.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Gamma-Aminobutyric Acid</condition>
  <condition>Anxiety</condition>
  <condition>Glutamate</condition>
  <condition>Emotion Regulation Abilities</condition>
  <arm_group>
    <arm_group_label>Galacto-oligosaccharides (GOS) Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this group will receive the daily dosage of galacto-oligosaccharides (GOS) prebiotic for 4 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Maltodextrin Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants in this group will receive the daily dosage of Maltodextrin placebo for 4 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Galacto-oligosaccharides</intervention_name>
    <description>GOS is a form of prebiotic, which enhance the growth of beneficial gut bacteria</description>
    <arm_group_label>Galacto-oligosaccharides (GOS) Group</arm_group_label>
    <other_name>GOS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Maltodextrin</intervention_name>
    <description>sugar based placebo</description>
    <arm_group_label>Maltodextrin Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Females&#xD;
&#xD;
          -  Aged between 18-25&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Clinical levels of anxiety and/ or co-morbid diagnoses (e.g. depression)&#xD;
&#xD;
          -  Current or previous neurological disorders&#xD;
&#xD;
          -  Current or previous psychiatric disorders&#xD;
&#xD;
          -  Current or previous gastrointestinal disorders&#xD;
&#xD;
          -  Current or previous endocrine disorders&#xD;
&#xD;
          -  Antibiotic use 3 months prior to the study&#xD;
&#xD;
          -  Regular use of pre- and probiotics, including 3 months prior to the study&#xD;
&#xD;
          -  Vegan diets&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kathrin Cohen Kadosh, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Surrey</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kathrin Cohen Kadosh, PhD</last_name>
    <phone>01483 68 3968</phone>
    <email>k.cohenkadosh@surrey.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Surrey</name>
      <address>
        <city>Guildford</city>
        <state>Surrey</state>
        <zip>GU2 7XH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kathrin Cohen-Kadosh, Phd</last_name>
      <phone>01483683968</phone>
      <email>k.cohenkadosh@surrey.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Nicola Johnstone, Phd</last_name>
      <email>nicola.johnstone@surrey.ac.uk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>February 1, 2019</study_first_submitted>
  <study_first_submitted_qc>February 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 8, 2019</study_first_posted>
  <last_update_submitted>April 28, 2021</last_update_submitted>
  <last_update_submitted_qc>April 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 29, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Surrey</investigator_affiliation>
    <investigator_full_name>Katherin Cohen-Kadosh</investigator_full_name>
    <investigator_title>Associate Professor in Developmental Cognitive Neuroscience</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03835468
org study id: PrebioticExtensionStudyGU2
nct id: NCT03835468
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The role of the microbiota-gut-brain axis in brain development and mental health
Anxiety disorders are debilitating conditions that carry enormous individual, social and
      economic costs. For example, it has been estimated that lifelong persistent mental health
      problems cost the UK taxpayer £8.6 billion annually. Many mental health problems have their
      onset in the transitional period from adolescence to early adulthood, possibly a result of
      the complex and concurrent hormonal, genetic, brain maturational and social changes during
      this period. Research has shown that brain development and maturation extends well into the
      third decade of life and that brain activation patterns in late adolescence and early
      adulthood still differ significantly from mature adults. In the recent years, the microbiome
      has emerged as a new and important factor that may increase the mental health risk for an
      individual. The intestine and the brain are intimately connected via the gut-brain axis,
      which involves bidirectional communication via neural, endocrine and immune pathways.
      Research in both the human and animal models has also highlighted the important role that
      intestinal microbiota play in regulating the brain, subsequent behaviour, and particularly in
      anxiety-like behaviour. Most importantly, it has been shown that the period of adolescence
      may be a critical window during development where microbiota help fine-tune the gut-brain
      axis related to stress responses and anxiety.

      The research proposed here will investigate the role of the microbiota-gut-brain axis in
      brain development and mental health. Specifically, the researchers will investigate the
      effect of prebiotic intake on mental health and well-being in late adolescence/early
      adulthood, with a particular focus on cortical excitability and connectivity in the emotion
      regulation brain network.

      This research will extend previous research into gut-brain interactions into the final years
      of adolescence. The period of adolescence is not only important with regards to fine-tuning
      emotion regulation networks, but also, as has been shown in recent work, critical for
      establishing healthy gut-brain communication patterns. Specifically, here we will investigate
      how prebiotic intake (Galacto-oligosaccharides) for 4 weeks affects cognitive functioning,
      psychological well-being and the underlying brain networks in a sample of 120 female
      undergraduate students (aged 18-25 years). Specifically, the proposed research has two main
      aims:

        1. To investigate how prebiotic intake affects cortical excitability and plasticity, such
           as inhibitory GABA/ excitatory glutamate levels in key emotion regulation brain
           networks.

        2. To investigate how prebiotic intake affects psychological functioning and well-being, in
           particular with regards to anxiety and thought control abilities.

      120 participants will be divided into two group of 60 participants, groups will be matched
      for age, handedness and socio-economic status. At each testing time (Time 1, 2 and 3),
      participants in both groups will undergo comprehensive behavioural and psychological testing
      to establish baseline measures of cognitive functioning and psychological well-being (such as
      anxiety levels).

      Each participant will also be asked to collect a stool sample at home for 16s rRNA sequencing
      of the microbiome at both testing times. Group 1 will receive a daily dosage of GOS over 4
      weeks, whereas group 2 will receive a placebo over the same period. In addition, participants
      from either group will also participate in a brain imaging session to assess the effect of
      prebiotic supplement intake on the functional responsiveness of emotion regulation brain
      networks.

      For this study, The researchers predict that the intervention group will show improvements in
      behavioural and psychological variables related to emotion regulation and anxiety in
      comparison to the placebo group (Hypothesis 1). Predictions also expect to observe decreased
      excitability in core emotion regulation brain regions such as the amygdala and prefrontal
      cortex, as assessed via 1H-magnet resonance spectroscopy (Hypothesis 2).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants will be randomly assigned into two groups. Group 1 will receive a daily dosage of GOS over 4 weeks, whereas group 2 will receive a placebo over the same period.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Changes in brain indices of emotion regulation abilities as a function of prebiotic intake 1
time frame: 4 weeks of intervention
description: Increase in brain-based metabolite concentrations (gamma-aminobutyric acid (GABA)) as assessed via Magnetic resonance spectroscopy in the prebiotics group in comparison to the placebo group.
measure: Changes in brain indices of emotion regulation abilities as a function of prebiotic intake 2
time frame: 4 weeks of intervention
description: Increase in functional connectivity in brain networks supporting emotion regulation abilities (as assessed via functional magnetic resonance imaging) in the prebiotics group in comparison to the placebo group.
measure: Changes in psychological measures of emotion regulation abilities as a function of prebiotic intake 1
time frame: 4 weeks of intervention
description: Decrease in Trait anxiety (State-Trait Anxiety Inventory, Spielberger, 1977) in the prebiotics group in comparison to the placebo group.. For this inventory, a lower overall score is the desired outcome.
measure: Changes in psychological measures of emotion regulation abilities as a function of prebiotic intake 2
time frame: 4 weeks of intervention
description: Decrease in Social Anxiety for adolescents (Social Anxiety Scales, La Greca, 1999) in the prebiotics group in comparison to the placebo group. For this scale, a lower overall score is the desired outcome.
measure: Changes in psychological measures of emotion regulation abilities as a function of prebiotic intake 3
time frame: 4 weeks of intervention
description: Increase in thought control ability (Thought control ability questionnaire, Luciano et al., 2005) in the prebiotics group in comparison to the placebo group.. For this questionnaire, a higher overall score is the desired outcome.
measure: Changes in gut microbiome composition as a function of prebiotic intake
time frame: 4 weeks of intervention
description: Increase in beneficial gut bacteria (percentage) in the prebiotics group in comparison to the placebo group. Based on stool sample analyses and microbiome sequencing.
measure: Changes in gut microbiome composition as a function of prebiotic intake
time frame: 4 weeks of intervention
description: Increase in diversity of gut bacteria in the prebiotics group (number of different bacteria) in comparison to the placebo group. Based on stool sample analyses and microbiome sequencing.
arm group label: Galacto-oligosaccharides (GOS) Group
arm group type: Experimental
description: Participants in this group will receive the daily dosage of galacto-oligosaccharides (GOS) prebiotic for 4 weeks
arm group label: Maltodextrin Group
arm group type: Placebo Comparator
description: Participants in this group will receive the daily dosage of Maltodextrin placebo for 4 weeks
intervention type: Dietary Supplement
intervention name: Galacto-oligosaccharides
description: GOS is a form of prebiotic, which enhance the growth of beneficial gut bacteria
arm group label: Galacto-oligosaccharides (GOS) Group
other name: GOS
intervention type: Dietary Supplement
intervention name: Maltodextrin
description: sugar based placebo
arm group label: Maltodextrin Group
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 25 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kathrin Cohen Kadosh, PhD
role: Principal Investigator
affiliation: University of Surrey
last name: Kathrin Cohen Kadosh, PhD
phone: 01483 68 3968
email: k.cohenkadosh@surrey.ac.uk
facility: 
status: Recruiting
contact: 
contact backup: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Surrey
investigator full name: Katherin Cohen-Kadosh
investigator title: Associate Professor in Developmental Cognitive Neuroscience
sharing ipd: No