Brain stimulation techniques are promising new treatments for addiction but additional research is needed to test their efficacy and to determine what explains their effects. This study examined the effects of transcranial magnetic stimulation on brain structure and function, as well as alcohol craving and use, among individuals with alcohol use disorder.
l
Alcohol use disorder is associated with several neural and biological changes that can hinder recovery. Repetitive transcranial magnetic stimulation is a technique that painlessly activates or suppresses activity in specific brain regions by sending short pulses of electrical current through the forehead.
Recent research suggests that transcranial magnetic stimulation to the frontal lobe (the part of the brain located near the forehead and responsible largely for higher level processes like planning and impulse control) may help reduce craving and risk of relapse among individuals with alcohol use disorder. However, the efficacy of transcranial magnetic stimulation treatment for addiction is not yet clear, given limited research and mixed findings, where some point to benefits and others do not. Moreover, little is known about the way in which transcranial magnetic stimulation affects the brain to produce these positive treatment outcomes.
Figure 1. Transcranial magnetic stimulation: activating or suppressing activity in a specific brain site by holding a magnet (AKA electromagnetic coil) against the head near that site and sending short pulses of electrical current through the magnet, which painlessly pass through the forehead and stimulate brain cells in the desired area.
One theory suggests that this stimulation technique may trigger changes to white matter in the brain, which is responsible for transmitting messages between different brain structures. Alcohol use disorder is associated with white matter deficits that often persist during early abstinence. Because these white matter deficits can hinder the transmission of messages in the brain they can, in turn, affect brain function and cognitive ability thereby impeding recovery progress.
Additional research is needed to determine if transcranial magnetic stimulation in frontal brain regions helps to promote positive changes in white matter, and if this accounts for the observed benefits of stimulation on craving and relapse risk. A better understanding of the mechanisms that underlie the benefits of transcranial magnetic stimulation could ultimately help optimize its use for the treatment of alcohol use disorder and help determine predictive markers for successful recovery and risk of relapse.
This study set out to determine if transcranial magnetic stimulation to frontal brain regions is associated with white matter changes in the brain, and if these changes are accompanied by reduced craving and alcohol use among individuals with alcohol use disorder.
This study was a secondary analysis of a double blind randomized clinical trial that evaluated the effects of deep transcranial magnetic stimulation on the brain, alcohol use, and craving among individuals with alcohol use disorder.
Thirty-seven adults with moderate to severe alcohol use disorder were recruited from the community in Israel. Participants were randomly assigned to an active group (n=18), which received the deep transcranial magnetic stimulation treatment, or a sham control group (n=19). The sham control was virtually identical to the intervention (i.e., with similar procedures and associated sensations in the scalp) but with a different coil in the helmet that did not stimulate relevant brain regions. Of note, study staff operating the device and participants were not aware which coil was used – that is whether they were in the intervention or sham control (i.e., they were “blinded” to condition). A sham condition like this helps researchers determine the effectiveness of the actual treatment, accounting for the possible effects of general study participation, including the belief that they will get better from the treatment, usually called a “placebo effect”. A “healthy control” group of age- and gender-matched adults without a history of alcohol use disorder also participated in the clinical trial.
Participants underwent magnetic resonance imaging brain scans before and after 3 weeks of transcranial magnetic stimulation or sham stimulation. High frequency, repetitive, transcranial magnetic stimulation treatment was delivered to frontal regions of the brain that are associated with the pathophysiology of alcohol use disorder. Stimulation was delivered in 30-minute sessions, 5 times per week, for a total of 15 sessions delivered over 3 weeks. All participants were followed up for 3 months, during which additional 30-minute transcranial magnetic stimulation (or sham, if in the sham group) maintenance-sessions were delivered at 1, 2, 4, 8, and 12 weeks after the end of the initial 3-weeks of treatment. Just before each transcranial magnetic stimulation treatment session, the researchers attempted to provoke craving in participants in an effort to activate craving-related brain circuits to prime them for change. To do this, participants were given a glass of their favorite alcoholic beverage and asked to hold it and smell it. The glass was then placed in front of them during the treatment session.
Craving and alcohol use were assessed prior to treatment (baseline), during treatment (weeks 1 to 3), and at every visit during the 3-month follow-up period (1, 2, 4, 8, 12 weeks post treatment). Past-week craving was assessed with a questionnaire (i.e. Penn Alcohol Craving Scale), with craving scores ranging from 0 (no craving) to 30 (strong craving). Alcohol use was assessed as the average drinking units (grams of pure alcohol per day) consumed over the 3-month follow-up period. Brain imaging scans were assessed for white matter integrity by evaluating fractional anisotropy, a measure of organized movement of water molecules in the brain that reflect the strength of connections between brain regions.
Healthy control participants and participants with alcohol use disorder – those randomly assigned to the intervention or sham control – were compared on baseline white matter integrity, as measured with fractional anisotropy. Participants with alcohol use disorder who received transcranial magnetic stimulation versus the sham condition were compared on: (1) changes in white matter integrity from baseline to the end of the 3-week treatment period, as measured with fractional anisotropy; (2) change in craving during treatment (from treatment week 1 to week 3); (3) change in average craving scores during treatment versus after treatment (average craving score over the 3-month follow-up period); (4) average amount of alcohol per day consumed over the 3-month follow-up period.
The researchers also identified the brain region with the greatest difference in white matter integrity at follow up between the active treatment and sham control group with alcohol use disorder, and identified the white matter tracts that go through these regions. They then looked at group differences in the strength of white matter tract connectivity between brain regions that these tracts communicate with, to determine if brain structure changes (i.e. fractional anisotropy) are accompanied by brain function changes (i.e. strength of connectivity). Increased white matter connectivity in these brain regions reflects stronger communication between them.
All participants with alcohol use disorder reported past-month alcohol use at baseline. Participants refrained from alcohol use for at least five days before the first brain stimulation treatment and before brain imaging scans were conducted, and all participants refrained from alcohol use during the initial 3-week treatment. The study used both self-report measures and biological verification to assess for alcohol use; individuals who used alcohol during this 3-week treatment period were withdrawn from the study. The intervention and sham control did not differ on demographic, clinical, or alcohol use characteristics at baseline. Compared to those with alcohol use disorder – the intervention and sham control groups – the healthy control group had less clinical symptomology (depression, anxiety, alcohol use) as would be expected, and one more year of education than the group with alcohol use disorder (12 vs. 13 years).
Transcranial magnetic stimulation counteracted reductions in white matter integrity during early abstinence
Consistent with prior studies, and relative to the control group of healthy adults, individuals with alcohol use disorder had reduced white matter integrity (i.e. lower fractional anisotropy) throughout most of the brain at baseline. When examining brain changes from baseline to post-treatment among individuals with alcohol use disorder, those who received the active treatment had no reductions in white matter integrity after 3 weeks of treatment, whereas the sham treated group showed small to medium-sized, ongoing reductions in white matter integrity. This difference was observed in the frontal lobe of the brain.
When looking at the function of these white matter connections among individuals with alcohol use disorder, the active treatment group had increased strength in the connection between brain regions after treatment, whereas the sham group did not change over time. Increased connectivity among the active treatment group was specifically observed between frontal brain regions and other brain structures that are connected by these white matter tracts.
Transcranial magnetic stimulation associated with lower levels of craving and alcohol use during and after treatment
The transcranial magnetic stimulation reduced craving during treatment (from week 1 to week 3 of treatment), a reduction which persisted post-treatment, whereas the sham treated group showed no difference in craving during treatment, but increased craving post-treatment. Although the magnitude of the reduction in craving is not directly reported in this study, the original trial study suggests a medium-sized advantage on craving for the intervention vs. sham group during treatment which was stable out to 3-month follow-up. The active treatment group also consumed less alcohol on average – also with a medium-sized difference – during the 3-month follow-up period than the sham group.
This study examined the effects of deep transcranial magnetic stimulation on the brain, alcohol use, and craving among individuals with alcohol use disorder. Findings suggest that deep transcranial magnetic stimulation of frontal brain regions that are associated with the pathophysiology of alcohol use disorder may help prevent ongoing reductions in white matter integrity and connectivity, and in turn, promote reductions in craving and alcohol consumption.
Individuals with alcohol use disorder often exhibit altered brain structure and function during active addiction and compared to healthy controls, with recent research suggesting ongoing reductions in white matter integrity that persist with at least six weeks of abstinence. This study replicates prior findings, demonstrating compromised white matter among recently abstinent individuals who received the sham treatment. These brain alterations have the potential to hinder recovery from alcohol use disorder, as they are thought to play a role in addiction processes like substance use and relapse. Because individuals with alcohol use disorder have a heightened risk of relapse during the initial months of alcohol abstinence, it is important to address the alcohol-associated brain changes that contribute to this increased risk.
Transcranial magnetic stimulation increases the activity of brain cells in certain brain regions, which might help the brain change in ways that maintain the speed and reliability of communication between brain regions during early abstinence. The brain regions affected by transcranial magnetic stimulation treatment in this study included regions that are associated with cognitive abilities like inhibitory control, planning, decision making, and working memory. These cognitive abilities play a role in recovery processes like motivational processing, risk avoidance, and recovery-oriented goal setting, that are essential for positive recovery outcomes. These brain regions are also thought to play a key role in the development and maintenance of alcohol use disorder. Thus, transcranial magnetic stimulation treatment during early abstinence may have protective effects against the deleterious brain changes that occur during early abstinence and withdrawal, which might help to support positive recovery outcomes like reduced alcohol use and craving.
The moderate-sized, but potentially meaningful, positive changes in craving that occurred during 3 weeks of intensive transcranial magnetic stimulation treatment appeared to be sustained over the 3-month follow-up period while heavy drinking days were greater in the sham vs. intervention group over time (e.g., both 40% at baseline but 15% sham vs. 5% intervention at the last follow-up). Importantly, individuals were still receiving transcranial magnetic stimulation (or the “sham” treatment) during the follow-up period, though it was delivered at a greatly reduced frequency. Therefore, the sustained effect of transcranial magnetic stimulation on brain and behavior might require ongoing maintenance treatment for individuals to experience ongoing benefit. Additional research is needed to determine the ideal “dosing” – the frequency and duration of transcranial magnetic stimulation treatment, how these parameters affect the maintenance/loss of the treatment’s effects, and whether the benefits of treatment can be maintained after it’s fully ceased. Studies that directly assess the relationship between changes in the brain’s white matter and alcohol craving/use after stimulation therapy will also help determine the specific treatment-induced neural changes that contribute to positive addiction-recovery outcomes. Transcranial magnetic stimulation is shown to be beneficial for several psychiatric symptoms, but its effectiveness for treating addiction is not yet clear, as the duration of treatment, brain area targeted for treatment, and outcome of interest vary across studies conducted to date. Nonetheless, this study reveals novel information about the possible underlying mechanisms of transcranial magnetic stimulation and its benefits for treating alcohol use disorder, which can ultimately yield new therapies and neurobiological targets for treating addiction.
Deep transcranial magnetic stimulation treatment of frontal brain regions among individuals with alcohol use disorder appeared to prevent ongoing reductions in white matter integrity and connectivity during early abstinence. The protective effects of treatment on the brain were accompanied by some medium-sized observed reductions in craving and alcohol consumption. This study highlights the potential of transcranial magnetic stimulation in treating alcohol use disorder and reveals new information about the potential brain changes that underlie behavioral changes induced by stimulation techniques. This area of study is new and future research will help determine the efficacy of transcranial magnetic stimulation for treating various addictive behaviors, the ideal parameters (e.g., duration, brain location) of treatment, and the duration of the treatment’s effects after treatment delivery ends.
Selim, M. K., Harel, M., De Santis, S., Perini, I., Sommer, W. H., Heilig, M., … & Canals, S. (2023). Repetitive deep TMS in alcohol dependent patients halts progression of white matter changes in early abstinence. Psychiatry and Clinical Neurosciences. doi: 10.1111/pcn.13624
l
Alcohol use disorder is associated with several neural and biological changes that can hinder recovery. Repetitive transcranial magnetic stimulation is a technique that painlessly activates or suppresses activity in specific brain regions by sending short pulses of electrical current through the forehead.
Recent research suggests that transcranial magnetic stimulation to the frontal lobe (the part of the brain located near the forehead and responsible largely for higher level processes like planning and impulse control) may help reduce craving and risk of relapse among individuals with alcohol use disorder. However, the efficacy of transcranial magnetic stimulation treatment for addiction is not yet clear, given limited research and mixed findings, where some point to benefits and others do not. Moreover, little is known about the way in which transcranial magnetic stimulation affects the brain to produce these positive treatment outcomes.
Figure 1. Transcranial magnetic stimulation: activating or suppressing activity in a specific brain site by holding a magnet (AKA electromagnetic coil) against the head near that site and sending short pulses of electrical current through the magnet, which painlessly pass through the forehead and stimulate brain cells in the desired area.
One theory suggests that this stimulation technique may trigger changes to white matter in the brain, which is responsible for transmitting messages between different brain structures. Alcohol use disorder is associated with white matter deficits that often persist during early abstinence. Because these white matter deficits can hinder the transmission of messages in the brain they can, in turn, affect brain function and cognitive ability thereby impeding recovery progress.
Additional research is needed to determine if transcranial magnetic stimulation in frontal brain regions helps to promote positive changes in white matter, and if this accounts for the observed benefits of stimulation on craving and relapse risk. A better understanding of the mechanisms that underlie the benefits of transcranial magnetic stimulation could ultimately help optimize its use for the treatment of alcohol use disorder and help determine predictive markers for successful recovery and risk of relapse.
This study set out to determine if transcranial magnetic stimulation to frontal brain regions is associated with white matter changes in the brain, and if these changes are accompanied by reduced craving and alcohol use among individuals with alcohol use disorder.
This study was a secondary analysis of a double blind randomized clinical trial that evaluated the effects of deep transcranial magnetic stimulation on the brain, alcohol use, and craving among individuals with alcohol use disorder.
Thirty-seven adults with moderate to severe alcohol use disorder were recruited from the community in Israel. Participants were randomly assigned to an active group (n=18), which received the deep transcranial magnetic stimulation treatment, or a sham control group (n=19). The sham control was virtually identical to the intervention (i.e., with similar procedures and associated sensations in the scalp) but with a different coil in the helmet that did not stimulate relevant brain regions. Of note, study staff operating the device and participants were not aware which coil was used – that is whether they were in the intervention or sham control (i.e., they were “blinded” to condition). A sham condition like this helps researchers determine the effectiveness of the actual treatment, accounting for the possible effects of general study participation, including the belief that they will get better from the treatment, usually called a “placebo effect”. A “healthy control” group of age- and gender-matched adults without a history of alcohol use disorder also participated in the clinical trial.
Participants underwent magnetic resonance imaging brain scans before and after 3 weeks of transcranial magnetic stimulation or sham stimulation. High frequency, repetitive, transcranial magnetic stimulation treatment was delivered to frontal regions of the brain that are associated with the pathophysiology of alcohol use disorder. Stimulation was delivered in 30-minute sessions, 5 times per week, for a total of 15 sessions delivered over 3 weeks. All participants were followed up for 3 months, during which additional 30-minute transcranial magnetic stimulation (or sham, if in the sham group) maintenance-sessions were delivered at 1, 2, 4, 8, and 12 weeks after the end of the initial 3-weeks of treatment. Just before each transcranial magnetic stimulation treatment session, the researchers attempted to provoke craving in participants in an effort to activate craving-related brain circuits to prime them for change. To do this, participants were given a glass of their favorite alcoholic beverage and asked to hold it and smell it. The glass was then placed in front of them during the treatment session.
Craving and alcohol use were assessed prior to treatment (baseline), during treatment (weeks 1 to 3), and at every visit during the 3-month follow-up period (1, 2, 4, 8, 12 weeks post treatment). Past-week craving was assessed with a questionnaire (i.e. Penn Alcohol Craving Scale), with craving scores ranging from 0 (no craving) to 30 (strong craving). Alcohol use was assessed as the average drinking units (grams of pure alcohol per day) consumed over the 3-month follow-up period. Brain imaging scans were assessed for white matter integrity by evaluating fractional anisotropy, a measure of organized movement of water molecules in the brain that reflect the strength of connections between brain regions.
Healthy control participants and participants with alcohol use disorder – those randomly assigned to the intervention or sham control – were compared on baseline white matter integrity, as measured with fractional anisotropy. Participants with alcohol use disorder who received transcranial magnetic stimulation versus the sham condition were compared on: (1) changes in white matter integrity from baseline to the end of the 3-week treatment period, as measured with fractional anisotropy; (2) change in craving during treatment (from treatment week 1 to week 3); (3) change in average craving scores during treatment versus after treatment (average craving score over the 3-month follow-up period); (4) average amount of alcohol per day consumed over the 3-month follow-up period.
The researchers also identified the brain region with the greatest difference in white matter integrity at follow up between the active treatment and sham control group with alcohol use disorder, and identified the white matter tracts that go through these regions. They then looked at group differences in the strength of white matter tract connectivity between brain regions that these tracts communicate with, to determine if brain structure changes (i.e. fractional anisotropy) are accompanied by brain function changes (i.e. strength of connectivity). Increased white matter connectivity in these brain regions reflects stronger communication between them.
All participants with alcohol use disorder reported past-month alcohol use at baseline. Participants refrained from alcohol use for at least five days before the first brain stimulation treatment and before brain imaging scans were conducted, and all participants refrained from alcohol use during the initial 3-week treatment. The study used both self-report measures and biological verification to assess for alcohol use; individuals who used alcohol during this 3-week treatment period were withdrawn from the study. The intervention and sham control did not differ on demographic, clinical, or alcohol use characteristics at baseline. Compared to those with alcohol use disorder – the intervention and sham control groups – the healthy control group had less clinical symptomology (depression, anxiety, alcohol use) as would be expected, and one more year of education than the group with alcohol use disorder (12 vs. 13 years).
Transcranial magnetic stimulation counteracted reductions in white matter integrity during early abstinence
Consistent with prior studies, and relative to the control group of healthy adults, individuals with alcohol use disorder had reduced white matter integrity (i.e. lower fractional anisotropy) throughout most of the brain at baseline. When examining brain changes from baseline to post-treatment among individuals with alcohol use disorder, those who received the active treatment had no reductions in white matter integrity after 3 weeks of treatment, whereas the sham treated group showed small to medium-sized, ongoing reductions in white matter integrity. This difference was observed in the frontal lobe of the brain.
When looking at the function of these white matter connections among individuals with alcohol use disorder, the active treatment group had increased strength in the connection between brain regions after treatment, whereas the sham group did not change over time. Increased connectivity among the active treatment group was specifically observed between frontal brain regions and other brain structures that are connected by these white matter tracts.
Transcranial magnetic stimulation associated with lower levels of craving and alcohol use during and after treatment
The transcranial magnetic stimulation reduced craving during treatment (from week 1 to week 3 of treatment), a reduction which persisted post-treatment, whereas the sham treated group showed no difference in craving during treatment, but increased craving post-treatment. Although the magnitude of the reduction in craving is not directly reported in this study, the original trial study suggests a medium-sized advantage on craving for the intervention vs. sham group during treatment which was stable out to 3-month follow-up. The active treatment group also consumed less alcohol on average – also with a medium-sized difference – during the 3-month follow-up period than the sham group.
This study examined the effects of deep transcranial magnetic stimulation on the brain, alcohol use, and craving among individuals with alcohol use disorder. Findings suggest that deep transcranial magnetic stimulation of frontal brain regions that are associated with the pathophysiology of alcohol use disorder may help prevent ongoing reductions in white matter integrity and connectivity, and in turn, promote reductions in craving and alcohol consumption.
Individuals with alcohol use disorder often exhibit altered brain structure and function during active addiction and compared to healthy controls, with recent research suggesting ongoing reductions in white matter integrity that persist with at least six weeks of abstinence. This study replicates prior findings, demonstrating compromised white matter among recently abstinent individuals who received the sham treatment. These brain alterations have the potential to hinder recovery from alcohol use disorder, as they are thought to play a role in addiction processes like substance use and relapse. Because individuals with alcohol use disorder have a heightened risk of relapse during the initial months of alcohol abstinence, it is important to address the alcohol-associated brain changes that contribute to this increased risk.
Transcranial magnetic stimulation increases the activity of brain cells in certain brain regions, which might help the brain change in ways that maintain the speed and reliability of communication between brain regions during early abstinence. The brain regions affected by transcranial magnetic stimulation treatment in this study included regions that are associated with cognitive abilities like inhibitory control, planning, decision making, and working memory. These cognitive abilities play a role in recovery processes like motivational processing, risk avoidance, and recovery-oriented goal setting, that are essential for positive recovery outcomes. These brain regions are also thought to play a key role in the development and maintenance of alcohol use disorder. Thus, transcranial magnetic stimulation treatment during early abstinence may have protective effects against the deleterious brain changes that occur during early abstinence and withdrawal, which might help to support positive recovery outcomes like reduced alcohol use and craving.
The moderate-sized, but potentially meaningful, positive changes in craving that occurred during 3 weeks of intensive transcranial magnetic stimulation treatment appeared to be sustained over the 3-month follow-up period while heavy drinking days were greater in the sham vs. intervention group over time (e.g., both 40% at baseline but 15% sham vs. 5% intervention at the last follow-up). Importantly, individuals were still receiving transcranial magnetic stimulation (or the “sham” treatment) during the follow-up period, though it was delivered at a greatly reduced frequency. Therefore, the sustained effect of transcranial magnetic stimulation on brain and behavior might require ongoing maintenance treatment for individuals to experience ongoing benefit. Additional research is needed to determine the ideal “dosing” – the frequency and duration of transcranial magnetic stimulation treatment, how these parameters affect the maintenance/loss of the treatment’s effects, and whether the benefits of treatment can be maintained after it’s fully ceased. Studies that directly assess the relationship between changes in the brain’s white matter and alcohol craving/use after stimulation therapy will also help determine the specific treatment-induced neural changes that contribute to positive addiction-recovery outcomes. Transcranial magnetic stimulation is shown to be beneficial for several psychiatric symptoms, but its effectiveness for treating addiction is not yet clear, as the duration of treatment, brain area targeted for treatment, and outcome of interest vary across studies conducted to date. Nonetheless, this study reveals novel information about the possible underlying mechanisms of transcranial magnetic stimulation and its benefits for treating alcohol use disorder, which can ultimately yield new therapies and neurobiological targets for treating addiction.
Deep transcranial magnetic stimulation treatment of frontal brain regions among individuals with alcohol use disorder appeared to prevent ongoing reductions in white matter integrity and connectivity during early abstinence. The protective effects of treatment on the brain were accompanied by some medium-sized observed reductions in craving and alcohol consumption. This study highlights the potential of transcranial magnetic stimulation in treating alcohol use disorder and reveals new information about the potential brain changes that underlie behavioral changes induced by stimulation techniques. This area of study is new and future research will help determine the efficacy of transcranial magnetic stimulation for treating various addictive behaviors, the ideal parameters (e.g., duration, brain location) of treatment, and the duration of the treatment’s effects after treatment delivery ends.
Selim, M. K., Harel, M., De Santis, S., Perini, I., Sommer, W. H., Heilig, M., … & Canals, S. (2023). Repetitive deep TMS in alcohol dependent patients halts progression of white matter changes in early abstinence. Psychiatry and Clinical Neurosciences. doi: 10.1111/pcn.13624
l
Alcohol use disorder is associated with several neural and biological changes that can hinder recovery. Repetitive transcranial magnetic stimulation is a technique that painlessly activates or suppresses activity in specific brain regions by sending short pulses of electrical current through the forehead.
Recent research suggests that transcranial magnetic stimulation to the frontal lobe (the part of the brain located near the forehead and responsible largely for higher level processes like planning and impulse control) may help reduce craving and risk of relapse among individuals with alcohol use disorder. However, the efficacy of transcranial magnetic stimulation treatment for addiction is not yet clear, given limited research and mixed findings, where some point to benefits and others do not. Moreover, little is known about the way in which transcranial magnetic stimulation affects the brain to produce these positive treatment outcomes.
Figure 1. Transcranial magnetic stimulation: activating or suppressing activity in a specific brain site by holding a magnet (AKA electromagnetic coil) against the head near that site and sending short pulses of electrical current through the magnet, which painlessly pass through the forehead and stimulate brain cells in the desired area.
One theory suggests that this stimulation technique may trigger changes to white matter in the brain, which is responsible for transmitting messages between different brain structures. Alcohol use disorder is associated with white matter deficits that often persist during early abstinence. Because these white matter deficits can hinder the transmission of messages in the brain they can, in turn, affect brain function and cognitive ability thereby impeding recovery progress.
Additional research is needed to determine if transcranial magnetic stimulation in frontal brain regions helps to promote positive changes in white matter, and if this accounts for the observed benefits of stimulation on craving and relapse risk. A better understanding of the mechanisms that underlie the benefits of transcranial magnetic stimulation could ultimately help optimize its use for the treatment of alcohol use disorder and help determine predictive markers for successful recovery and risk of relapse.
This study set out to determine if transcranial magnetic stimulation to frontal brain regions is associated with white matter changes in the brain, and if these changes are accompanied by reduced craving and alcohol use among individuals with alcohol use disorder.
This study was a secondary analysis of a double blind randomized clinical trial that evaluated the effects of deep transcranial magnetic stimulation on the brain, alcohol use, and craving among individuals with alcohol use disorder.
Thirty-seven adults with moderate to severe alcohol use disorder were recruited from the community in Israel. Participants were randomly assigned to an active group (n=18), which received the deep transcranial magnetic stimulation treatment, or a sham control group (n=19). The sham control was virtually identical to the intervention (i.e., with similar procedures and associated sensations in the scalp) but with a different coil in the helmet that did not stimulate relevant brain regions. Of note, study staff operating the device and participants were not aware which coil was used – that is whether they were in the intervention or sham control (i.e., they were “blinded” to condition). A sham condition like this helps researchers determine the effectiveness of the actual treatment, accounting for the possible effects of general study participation, including the belief that they will get better from the treatment, usually called a “placebo effect”. A “healthy control” group of age- and gender-matched adults without a history of alcohol use disorder also participated in the clinical trial.
Participants underwent magnetic resonance imaging brain scans before and after 3 weeks of transcranial magnetic stimulation or sham stimulation. High frequency, repetitive, transcranial magnetic stimulation treatment was delivered to frontal regions of the brain that are associated with the pathophysiology of alcohol use disorder. Stimulation was delivered in 30-minute sessions, 5 times per week, for a total of 15 sessions delivered over 3 weeks. All participants were followed up for 3 months, during which additional 30-minute transcranial magnetic stimulation (or sham, if in the sham group) maintenance-sessions were delivered at 1, 2, 4, 8, and 12 weeks after the end of the initial 3-weeks of treatment. Just before each transcranial magnetic stimulation treatment session, the researchers attempted to provoke craving in participants in an effort to activate craving-related brain circuits to prime them for change. To do this, participants were given a glass of their favorite alcoholic beverage and asked to hold it and smell it. The glass was then placed in front of them during the treatment session.
Craving and alcohol use were assessed prior to treatment (baseline), during treatment (weeks 1 to 3), and at every visit during the 3-month follow-up period (1, 2, 4, 8, 12 weeks post treatment). Past-week craving was assessed with a questionnaire (i.e. Penn Alcohol Craving Scale), with craving scores ranging from 0 (no craving) to 30 (strong craving). Alcohol use was assessed as the average drinking units (grams of pure alcohol per day) consumed over the 3-month follow-up period. Brain imaging scans were assessed for white matter integrity by evaluating fractional anisotropy, a measure of organized movement of water molecules in the brain that reflect the strength of connections between brain regions.
Healthy control participants and participants with alcohol use disorder – those randomly assigned to the intervention or sham control – were compared on baseline white matter integrity, as measured with fractional anisotropy. Participants with alcohol use disorder who received transcranial magnetic stimulation versus the sham condition were compared on: (1) changes in white matter integrity from baseline to the end of the 3-week treatment period, as measured with fractional anisotropy; (2) change in craving during treatment (from treatment week 1 to week 3); (3) change in average craving scores during treatment versus after treatment (average craving score over the 3-month follow-up period); (4) average amount of alcohol per day consumed over the 3-month follow-up period.
The researchers also identified the brain region with the greatest difference in white matter integrity at follow up between the active treatment and sham control group with alcohol use disorder, and identified the white matter tracts that go through these regions. They then looked at group differences in the strength of white matter tract connectivity between brain regions that these tracts communicate with, to determine if brain structure changes (i.e. fractional anisotropy) are accompanied by brain function changes (i.e. strength of connectivity). Increased white matter connectivity in these brain regions reflects stronger communication between them.
All participants with alcohol use disorder reported past-month alcohol use at baseline. Participants refrained from alcohol use for at least five days before the first brain stimulation treatment and before brain imaging scans were conducted, and all participants refrained from alcohol use during the initial 3-week treatment. The study used both self-report measures and biological verification to assess for alcohol use; individuals who used alcohol during this 3-week treatment period were withdrawn from the study. The intervention and sham control did not differ on demographic, clinical, or alcohol use characteristics at baseline. Compared to those with alcohol use disorder – the intervention and sham control groups – the healthy control group had less clinical symptomology (depression, anxiety, alcohol use) as would be expected, and one more year of education than the group with alcohol use disorder (12 vs. 13 years).
Transcranial magnetic stimulation counteracted reductions in white matter integrity during early abstinence
Consistent with prior studies, and relative to the control group of healthy adults, individuals with alcohol use disorder had reduced white matter integrity (i.e. lower fractional anisotropy) throughout most of the brain at baseline. When examining brain changes from baseline to post-treatment among individuals with alcohol use disorder, those who received the active treatment had no reductions in white matter integrity after 3 weeks of treatment, whereas the sham treated group showed small to medium-sized, ongoing reductions in white matter integrity. This difference was observed in the frontal lobe of the brain.
When looking at the function of these white matter connections among individuals with alcohol use disorder, the active treatment group had increased strength in the connection between brain regions after treatment, whereas the sham group did not change over time. Increased connectivity among the active treatment group was specifically observed between frontal brain regions and other brain structures that are connected by these white matter tracts.
Transcranial magnetic stimulation associated with lower levels of craving and alcohol use during and after treatment
The transcranial magnetic stimulation reduced craving during treatment (from week 1 to week 3 of treatment), a reduction which persisted post-treatment, whereas the sham treated group showed no difference in craving during treatment, but increased craving post-treatment. Although the magnitude of the reduction in craving is not directly reported in this study, the original trial study suggests a medium-sized advantage on craving for the intervention vs. sham group during treatment which was stable out to 3-month follow-up. The active treatment group also consumed less alcohol on average – also with a medium-sized difference – during the 3-month follow-up period than the sham group.
This study examined the effects of deep transcranial magnetic stimulation on the brain, alcohol use, and craving among individuals with alcohol use disorder. Findings suggest that deep transcranial magnetic stimulation of frontal brain regions that are associated with the pathophysiology of alcohol use disorder may help prevent ongoing reductions in white matter integrity and connectivity, and in turn, promote reductions in craving and alcohol consumption.
Individuals with alcohol use disorder often exhibit altered brain structure and function during active addiction and compared to healthy controls, with recent research suggesting ongoing reductions in white matter integrity that persist with at least six weeks of abstinence. This study replicates prior findings, demonstrating compromised white matter among recently abstinent individuals who received the sham treatment. These brain alterations have the potential to hinder recovery from alcohol use disorder, as they are thought to play a role in addiction processes like substance use and relapse. Because individuals with alcohol use disorder have a heightened risk of relapse during the initial months of alcohol abstinence, it is important to address the alcohol-associated brain changes that contribute to this increased risk.
Transcranial magnetic stimulation increases the activity of brain cells in certain brain regions, which might help the brain change in ways that maintain the speed and reliability of communication between brain regions during early abstinence. The brain regions affected by transcranial magnetic stimulation treatment in this study included regions that are associated with cognitive abilities like inhibitory control, planning, decision making, and working memory. These cognitive abilities play a role in recovery processes like motivational processing, risk avoidance, and recovery-oriented goal setting, that are essential for positive recovery outcomes. These brain regions are also thought to play a key role in the development and maintenance of alcohol use disorder. Thus, transcranial magnetic stimulation treatment during early abstinence may have protective effects against the deleterious brain changes that occur during early abstinence and withdrawal, which might help to support positive recovery outcomes like reduced alcohol use and craving.
The moderate-sized, but potentially meaningful, positive changes in craving that occurred during 3 weeks of intensive transcranial magnetic stimulation treatment appeared to be sustained over the 3-month follow-up period while heavy drinking days were greater in the sham vs. intervention group over time (e.g., both 40% at baseline but 15% sham vs. 5% intervention at the last follow-up). Importantly, individuals were still receiving transcranial magnetic stimulation (or the “sham” treatment) during the follow-up period, though it was delivered at a greatly reduced frequency. Therefore, the sustained effect of transcranial magnetic stimulation on brain and behavior might require ongoing maintenance treatment for individuals to experience ongoing benefit. Additional research is needed to determine the ideal “dosing” – the frequency and duration of transcranial magnetic stimulation treatment, how these parameters affect the maintenance/loss of the treatment’s effects, and whether the benefits of treatment can be maintained after it’s fully ceased. Studies that directly assess the relationship between changes in the brain’s white matter and alcohol craving/use after stimulation therapy will also help determine the specific treatment-induced neural changes that contribute to positive addiction-recovery outcomes. Transcranial magnetic stimulation is shown to be beneficial for several psychiatric symptoms, but its effectiveness for treating addiction is not yet clear, as the duration of treatment, brain area targeted for treatment, and outcome of interest vary across studies conducted to date. Nonetheless, this study reveals novel information about the possible underlying mechanisms of transcranial magnetic stimulation and its benefits for treating alcohol use disorder, which can ultimately yield new therapies and neurobiological targets for treating addiction.
Deep transcranial magnetic stimulation treatment of frontal brain regions among individuals with alcohol use disorder appeared to prevent ongoing reductions in white matter integrity and connectivity during early abstinence. The protective effects of treatment on the brain were accompanied by some medium-sized observed reductions in craving and alcohol consumption. This study highlights the potential of transcranial magnetic stimulation in treating alcohol use disorder and reveals new information about the potential brain changes that underlie behavioral changes induced by stimulation techniques. This area of study is new and future research will help determine the efficacy of transcranial magnetic stimulation for treating various addictive behaviors, the ideal parameters (e.g., duration, brain location) of treatment, and the duration of the treatment’s effects after treatment delivery ends.
Selim, M. K., Harel, M., De Santis, S., Perini, I., Sommer, W. H., Heilig, M., … & Canals, S. (2023). Repetitive deep TMS in alcohol dependent patients halts progression of white matter changes in early abstinence. Psychiatry and Clinical Neurosciences. doi: 10.1111/pcn.13624
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