Negative Type; Schizophrenic, Schizo Affective Disorder, Schizophrenia
Conditions
Keywords
brain, networks, schizophrenia
Brief summary
The main purpose of this study is to learn how transcranial magnetic stimulation (TMS) helps improve negative symptoms of schizophrenia. These 'negative symptoms' include anhedonia (the inability to enjoy things), low motivation, and decreased facial expression. TMS is a noninvasive way of stimulating the brain. TMS uses a magnetic field to cause changes in activity in the brain. The magnetic field is produced by a coil that is held next to the scalp. In this study we will be stimulating the brain to learn more about how TMS may improve these symptoms from schizophrenia.
Detailed description
This study proposes to test the hypothesis that the medication refractory experiential (anhedonia and amotivation) and expressive deficits named 'negative symptoms' are mediated by network pathophysiology and the functional connectivity of a cerebellar-prefrontal cortical network mediates the severity of these deficits. To accomplish this participants will be recruited who are diagnosed with schizophrenia or schizoaffective disorder who demonstrate negative symptoms despite stable outpatient treatment. Participants will undergo an initial screening session to complete informed consent and undergo baseline assessments of negative symptom severity. These assessments include reporter-based measures such as the Positive And Negative Syndrome Scale (PANSS) as well as quantitative tests of amotivation/anhedonia and diminished expressivity. Participants will then undergo an MRI scan that includes structural and resting state functional magnetic resonance imaging (rsfMRI). These rsfMRI images will be used to isolate individual resting-state networks for targeting of rTMS modulation. Participants will then undergo five days of twice daily rTMS sessions in one of the four arms of this study. One week after the last rTMS session, Participants will undergo follow-up MRI imaging and the same assessments described above. Aims: Aim 1: To determine if network dysconnectivity is causally linked to negative symptom severity and if amelioration of this dysconnectivity results in reduced symptom severity. Symptom severity will be measured via both reporter-based and quantitative measures. Aim 2: To determine if the relationship between functional connectivity and symptom severity arises from interactions between specific nodes of the default mode network (DMN): the cerebellum and DLPFC, or is the result of interactions between multiple nodes in the DMN (both cerebral and cerebellar). Exploratory Aim: As an exploratory aim, additional genetic data will be collected which may be related to TMS efficacy. Hypothesis: Brain-derived neurotrophic factor (BDNF) homozygous val-allele carriers of the val66met BDNF gene will show greater response than met-carriers.
Interventions
DEVICErepetitive Transcranial Magnetic Stimulation (rTMS)
rTMS is a technique of TMS that allows the selective external manipulation of neural activity in a non-invasive manner. During TMS, a rapidly changing current is passed through an insulated coil placed against the scalp. This generates a temporary magnetic field that in turn induces electrical current in neurons and allows the modulation of neural circuitry. The combination of TMS with fMRI allows the selective targeting and modulation of brain networks. The repeated application of rTMS can cause long term changes in behavior and task performance that is reflected in altered brain network connectivity. The pattern of rTMS will consist of either: intermittent Theta Burst Stimulation (iTBS) pattern consisting of 2 s trains of 3 pulses at 50 Hz, repeated at 5 Hz, every 10s for a total of 600 pulses. OR sham stimulation
Sponsors
Beth Israel Deaconess Medical Center
Mclean Hospital
Harvard University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The subjects, care providers, investigators and outcome assessors will all be blinded as to the randomization sequence, and thus will be blinded as to sham vs active TMS status. Blinding codes are used to determine which side of an active/passive Magpro coil (cool B65 A/P, Magventure A/S, Denmark) is used for stimulation.
Intervention model description
There will be four groups: an active DLPFC TMS group, an active TMS cerebellum group, a sham DLPFC group, and a sham cerebellum group. Participants will be randomized to one of these group groups, and they will receive that type of stimulation for the entire study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Age between 18-55 years * At pre-visit screening (see attached phone screening questionnaire): participants must report that they have been given a diagnosis of schizophrenia or schizoaffective disorder by a mental health professional * Must be able to read, speak, and understand English * Must be judged by study staff to be capable of completing the study procedures * Diagnosis of schizophrenia or schizoaffective disorder according to DSM-V criteria and confirmed by SCID * Participants will be in stable outpatient treatment with no recent (within the past 30 days) hospitalizations or changes in their mediation regimens
Exclusion criteria
* DSM-V intellectual disability * substance use disorder within the past three months * Ambidexterity (the EEfRT task assumes participants are not ambidextrous) * Any history of progressive or genetic neurological disorder (e.g. Parkinson's disease, multiple sclerosis, tubular sclerosis, Alzheimer's Disease) or acquired neurological disease (e.g. stroke, traumatic brain injury, tumor), including intracranial lesions * History of head trauma resulting in any loss of consciousness (\>15 minutes) or neurological sequelae * Current history of poorly controlled headaches including chronic medication for migraine prevention * History of fainting spells of unknown or undetermined etiology that might constitute seizures * History of seizures, diagnosis of epilepsy, or immediate (1st degree relative) family history epilepsy with the exception of a single seizure of benign etiology (e.g. febrile seizures) in the judgment of a board-certified neurologist * Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.) * Any metal in the brain or skull (excluding dental fillings) or elsewhere in the body unless cleared by the responsible covering MD (e.g. MRI compatible joint replacement) * Any devices such as pacemaker, medication pump, nerve stimulator, TENS unit, ventriculo-peritoneal shunt unless cleared by the responsible covering MD * All female participants of child bearing age will be required to have a pregnancy test; any participant who is pregnant will not be enrolled in the study * Medications will be reviewed by the responsible covering physician and a decision about inclusion will be made based on the participant's past medical history, drug dose, history of recent medication changes or duration of treatment, and use of CNS active drugs. The published TMS guidelines review of medications to be considered with rTMS will be taken into consideration given their described effects on cortical excitability measures. * Any changes in medications or hospitalizations within the past 30 days. * Subjects who, in the investigator's opinion, might not be suitable for the study or would be unable to tolerate the study visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Negative Symptom Severity | Before treatment (Baseline) and 1 week post treatment | We will evaluate the effect of sham vs active rTMS on The Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Negative Symptom total score. This score is the sum of seven questions on the PANSS questionnaire (named N1-N7). Each question is scored from 1-7 for a total score per individual ranging from 7-49. On this scale higher numbers indicate great symptomology |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebellar - Prefrontal Functional Connectivity | Before treatment (Baseline) and 1 week post treatment | We will evaluate the effect of sham vs active rTMS on cerebellar-prefrontal cortex functional connectivity in the group with Cerebellar targeted rTMS and in the group with DLPFC targeted rTMS |
| Change in Auditory Hallucination Severity | Before treatment (Baseline) and 1 week post treatment | We will evaluate the effect of sham vs active rTMS on the frequency and severity of auditory hallucinations in the group with Cerebellar targeted rTMS. PANSS P3 Hallucination Severity is a single question on the Positive and Negative Syndrome Scale. Question P3 assesses hallucination severity and ranges from 1 (least symptomatic) to 7 (most symptomatic) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRoscoe Brady, MD, PhD
Beth Israel Deaconess Medical Center
Participant flow
Pre-assignment details
47 participants agreed to participate in the study following completion of the informed consent process. During subsequent study procedures, 18 consented participants were found ineligible to continue in the study and were not randomized to a treatment arm. Participants were randomized into "Active Cerebellum rTMS" and "Sham Cerebellum rTMS" arms but the study concluded before participants could be enrolled into the "Active DLPFC rTMS" and "Sham DLPFC rTMS"
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 35.8 years STANDARD_DEVIATION 7.7 |
| PANSS negative symptoms total | 15.44 PANSS negative symptoms total STANDARD_DEVIATION 4.242 |
| PANSS P3 Hallucination Severity | 2.75 units on a scale STANDARD_DEVIATION 1.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 29 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 16 |
| other Total, other adverse events | 7 / 13 | 9 / 16 |
| serious Total, serious adverse events | 0 / 13 | 0 / 16 |
Outcome results
None listed