Cigarette smoking rates are extremely high in persons with schizophrenia and this increases the risk of disease and death due to tobacco-related disorders. One of the features of schizophrenia is reduced cognitive abilities, such as poor attention and memory. It is thought that people with schizophrenia smoke cigarettes to reduce these cognitive problems, as nicotine can improve cognitive function in these people. When people with schizophrenia stop smoking it causes further cognitive difficulties, which makes quitting harder for them compared to people without schizophrenia. A method called repetitive transcranial magnetic stimulation (rTMS) allows clinicians to give repeated magnetic pulses through the scalp to cause changes in brain activity and behaviour. rTMS can improve cognitive function in people with schizophrenia. Studies have also shown that rTMS can reduce tobacco craving and consumption of cigarettes. Therefore, we believe that rTMS will improve the cognitive deficits observed during cigarette smoking abstinence and help reduce cravings for cigarettes. Ultimately, rTMS may help smokers with schizophrenia who can't quit smoking with available treatments. This study will examine the effect of rTMS on tobacco cravings and cognitive problems produced by overnight abstinence from cigarette smoking in persons with schizophrenia in comparison to people without mental illness who smoke. Important information about the potential of rTMS for the treatment of cognitive deficits and tobacco addiction in schizophrenia will be obtained. Providing more effective smoking cessation treatments in people with schizophrenia may lead to improved physical and mental health for these patients, who are extremely susceptible to tobacco addiction and tobacco-related illness.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
27
Subjects will undergo two testing weeks (active and sham rTMS treatment), washout period ≥ 1 month between the testing weeks. rTMS treatment sessions will take place twice daily on days 1-3 of each test week. Active treatment will be delivered at 90% resting motor threshold intensity. Stimulation will be administered at 20 Hz with 25 stimulation trains of 30 stimuli each with an inter-train interval of 30 sec at equivalent stimulation parameters as those used in our pilot trial. Stimulation Site: Advanced neuronavigation methods will be used to target rTMS to the dorsolateral prefrontal cortex following a T1 weighted MRI scan.
Subjects will undergo two testing weeks (active and sham rTMS treatment) administered in a randomized order, to which both experimenter and participant will be blind. There will be a washout period of at least one month between the testing weeks to ensure that any changes in cortical function induced by rTMS have returned to baseline. rTMS treatment sessions will take place twice daily on days 1-3 of each test week. Sham Condition: A single-wing tilt rTMS coil position producing somatic sensation (contraction of scalp muscles) with minimal direct brain effects will be used (same stimulation parameters and site as active condition).
Centre for Addiction and Mental Health
Toronto, Ontario, Canada
Cigarette craving as assessed by Tiffany Questionnaire for Smoking Urges (TQSU)
Craving will be assessed using the TQSU, a 32-item list of signs and symptoms of nicotine cravings and urges to smoke which subjects rate how strongly they agree or disagree with the statements on a scale of 1 (strongly disagree) to 7 (strongly agree).
Time frame: Pre- and post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
Cigarette withdrawal using the Minnesota Nicotine Withdrawal Scale (MNWS)
Withdrawal will be assessed using the MNWS on which subjects self-report nicotine withdrawal symptoms including nicotine craving, irritability, anxiety, difficulty concentrating, restlessness, increased appetite or weight gain, depressed mood, and insomnia on a 5-point scale of 1 (none) to 5 (severe). Note: The internal consistencies and test-retest reliability of the MNWS, TQSU and FTND in schizophrenia are comparable to those observed in controls.
Time frame: Pre- and post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
Expired breath carbon monoxide (CO) levels
Expired Breath CO (in parts per million; ppm) will be used to biochemically verify smoking status.
Time frame: Pre- and post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 1 and 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
Plasma nicotine/cotinine levels
Plasma nicotine and cotinine levels will provide and objective measurement of cigarette smoking. Assays will be performed by the CAMH Clinical Laboratory using GC/MS/MS procedures which have been adapted from published procedures.
Time frame: Pre- and post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
Continuous Performance Test-X (CPT-X)
The CPT-X is designed to measure sustained attention and response inhibition. Participants press the space bar as quickly as possible after each letter is presented except when the letter 'X' is presented. Common measures reported include % Hits, % Omissions, % Commissions, Reaction Time, Reactions Time Variability and an Attentional Index (d') Duration: 15 minutes
Time frame: Post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
N-back
The N-back is designed to measure working memory (WM). This task requires continuous upgrades of the memory store and is suited to studying varying levels of working memory load. Task-load will be parametrically manipulated by varying the interval between targets requiring responses (i.e., 1-back, 3-back) according to previously published methods. The dependent variables of interest will include the average performance and reaction times. Duration:45 minutes.
Time frame: Post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
Spatial Delayed Response (SDR)
The SDR is designed to measure visuospatial working memory (VSWM). Subjects focus on a central fixation cross on a computer screen. While fixated (staring at the cross), a dot-shaped cue flashes in one of 32 possible locations towards the outer edge of the screen. Then a delay period occurs (5, 15 or 30 seconds). After the delay, the fixation cross returns and the subjects must point on the computer screen where they remember seeing the dot cue. Results are reported as the averaged "distance from target" in cm for the 10 trials at each delay condition. Duration: 15 minutes.
Time frame: Post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
EEG recording during performance of N-back Task
EEG recording during performance of N-back Task: EEG data will be collected using the methods reported in by our lab. A 64-electrode cap and Synamps2 DC-coupled EEG system (Compumedics) will be used. Evoked γ-power from the frontal electrodes will be measured while the participants complete the N-back task.
Time frame: Post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
Hopkins Verbal Learning Test Revised (HVLT-R)
The HVLT measures verbal learning and memory. The HVLT-R is a verbal list-learning test designed to measure the acquisition of new verbal information using a 12-item word list.Duration: 10 minutes.
Time frame: Post rTMS/sham treatment week 1 and 2: at baseline smoking as usual (day 2), following over-night smoking abstinence (day 3am) and smoking reinstatement (day 3pm)
Smoking Topography
Smoking patterns will be assessed by measuring aspects of smoking topography (using the CReSS system) such as latency to puff, puff frequency, puff volume, puff duration, inter-puff interval, depth of inhalation and inter-cigarette interval which are postulated to be in vivo measures of smoking reinforcement.The CReSS calculates and stores a number of measures including total number of puffs smoked per session, total puff volume per cigarette, puffs per cigarette, duration of inter-puff interval, average maximum puff velocity, average puff volume and average puff duration.
Time frame: Week 1 and 2: At baseline, day 2 when smoking as usual and following over-night smoking abstinence day 3
Spontaneous smoking
Spontaneous Smoking will be assessed by self-report using timeline followback (TLFB) methods.
Time frame: Week 1 and 2: Pre- and post rTMS/sham treatment at baseline day 1 and 2 when smoking as usual) and following over-night smoking abstinence day 3
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