Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is characterized by inattention, hyperactivity, and impulsivity. It is one of the most common mental disorders among children, with a prevalence of approximately 5% [1]. Up to 65% of patients with ADHD have symptoms that persist into adulthood [2], resulting in long-lasting psychosocial impairment [3,4]. Patients with ADHD show increased reward-seeking behavior [5] and are at increased risk of substance use disorder [6]. Moreover, approximately 23% of patients with substance use disorder have been found to have ADHD [7]. Cannabis is one of the most commonly used illegal or controlled substances worldwide [8], with high rates of use in adolescence and early adulthood [9]. One study found that children with ADHD had almost three times higher odds of having ever used marijuana and were 1.5 times more likely to become cannabis-dependent than those without ADHD [6]. In another study, the rate of cannabis use during 8 years of follow-up was significantly higher in adolescents who had a diagnosis of ADHD in childhood (32%) than in their typically developing counterparts (24%) [10]. More specifically, increased odds of lifetime cannabis use (odds ratio = 2.78) and diagnosis with cannabis use disorder during young adulthood (odds ratio = 1.51) were reported for people diagnosed with ADHD in childhood according to meta-analyses [6,11].The thalamus is an important component of the cortico-striato-thalamo-cortical circuit, disruption of which has been implicated in ADHD [12]. Preschool-aged children with ADHD have reduced subcortical volumes, including in the thalamus [13], although this finding was not replicated in a large sample of older children [14]. Other studies found that adults with a diagnosis of ADHD in childhood had decreased brain activity, including in the thalamus, during tasks involving inhibitory control and cognitive flexibility [15], which may be associated with substance use disorder [16–18]. Moreover, resting-state functional connectivity between the thalamus and putamen is significantly greater in children with ADHD than in typically developing children [19,20]. The thalamus may play an important role in addiction, especially in terms of reduced response inhibition and enhanced salience to drug cues [21]. Decreased thalamic resting-state functional connectivity has been observed in smokers, long-term abstinent alcoholics, and young adults with untreated cannabis use disorder [22–24]. Furthermore, thalamic volumes have been found to be bilaterally reduced in users of synthetic cannabinoids [25]. Methylphenidate, which is one of the medications most commonly used in ADHD, significantly increases resting-state connectivity between the thalamus and the cerebellum in both cannabis abusers and healthy controls, whereas methylphenidate-induced increases in thalamic metabolism were blunted in participants with cannabis use disorder in comparison with controls [26].In summary, both ADHD and cannabis use may be associated with resting-state functional connectivity of the thalamus. However, little is known about the role of functional thalamic connectivity in the increased risk of cannabis use in patients with ADHD, and few studies have addressed this issue. Therefore, we aimed to explore the relationship between ADHD and cannabis use in the brain, with a special focus on the thalamus. Based on the findings of previous studies [22–24,26], we hypothesized that thalamic connectivity would be decreased in cannabis users with a childhood diagnosis of ADHD. In this study, we investigated resting-state functional thalamic connectivity in adults who had been diagnosed with ADHD in childhood according to their cannabis use status.

Methods

Study design and participants

The Multimodal Treatment Study of ADHD (MTA) was initiated as a randomized clinical trial funded by the National Institute of Mental Health, and the participants were subsequently followed up in a longitudinal study. In this study, we analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data obtained from the publicly available Addiction Connectome Preprocessed Initiative (ACPI) MTA database (http://fcon_1000.projects.nitrc.org/indi/ACPI/html/index.html), which is supported by the National Institute on Drug Abuse. The complete dataset consisted of MRI scans and phenotypic information collected from six different sites. The phenotypic information released from the ACPI database included age, sex, intelligence quotient, data collection site, handedness, ethnicity, education level, being a smoker or not, and whether currently taking ADHD medication, in addition to the group assignment for ADHD and marijuana use. Other potentially important details such as anxiety, depression, use of substances other than marijuana and tobacco, or treatment assignment in the original MTA were not available from the released dataset.In the original MTA, participants met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for ADHD combined type, based on the Diagnostic Interview Schedule for Children (DISC), parent report, which was supplemented with up to two symptoms reported by children’s teachers based on the Swanson, Nolan and Pelham-IV (SNAP-IV) questionnaire when falling just below the DISC diagnostic threshold [27]. In addition, age-matched and sex-matched classmates of children with ADHD were recruited as a local normative comparison group (LNCG) [28]. In the ACPI dataset, a total of 129 study participants were classified into four groups: ADHD marijuana users (group 1, 39 males and 3 females), ADHD marijuana non-users (group 2, 34 males and 12 females), LNCG marijuana users (group 3, 17 males and 3 females), and LNCG marijuana non-users (group 4, 14 males and 7 females). Participants were classified as marijuana users if they used marijuana once per month or more and non-users if they had used marijuana fewer than four times during the past year, which was identified based on self-reported cannabis use using the Substance Use Questionnaire and Substance Use Recency Questionnaire [29]. In line with the high male predominance in ADHD and in cannabis use [1,30], there were significant differences in the male-to-female ratio among groups, which could have had a serious confounding influence on our findings; therefore, we only included male participants in our analysis. Limited information was available on the scanning parameters via the ACPI database; however, more information can be found in a report by the data collectors (i.e., the MTA Neuroimaging Group) [29].Informed written consent was obtained from all participating families in the original MTA [27]. This study used deidentified data and was granted exemption from a review by the Institutional Review Board at the Seoul National University Hospital. All methods were performed in accordance with the relevant guidelines and regulations.

Image processing

We used rs-fMRI data that had been preprocessed using Advanced Normalization Tools (ANTs) software (http://stnava.github.io/ANTs/) and released by the ACPI. The ACPI provides four different versions of the preprocessed data according to motion correction (with or without scrubbing) and nuisance correction (with and without global signal regression). To ensure the robustness of our findings, we used all four versions of the preprocessed datasets in our analyses. All steps in the processing pipeline are described at http://fcon_1000.projects.nitrc.org/indi/ACPI/html/preproc.html.Given that head motion in the scanner has been a serious confounder in rs-fMRI studies [31,32], we excluded participants who had fewer than 100 scans after scrubbing. This resulted in sample sizes of 18, 15, 9, and 7 male participants, respectively, in groups 1, 2, 3, and 4. Based on our hypothesis and interest in the implication of thalamic connectivity in cannabis use among individuals with ADHD, and considering the small sample size of the other two groups representing non-ADHD participants, a comparison of thalamic functional connectivity between the first two groups was the focus in this study. Among the 25 female participants included in the ACPI dataset, the exclusion of participants who had fewer than 100 scans after scrubbing resulted in sample sizes of 0, 7, 2, and 3 female participants, respectively, in groups 1, 2, 3, and 4. Thus, we decided to focus on male participants as including both sexes in the analysis would have caused a severe imbalance in the male-to-female ratio, and the absence of female participants in group 1, in particular, limited our ability to match the number of each sex among groups.This final sample was equally applied to the analysis of all four versions of the preprocessed datasets. Regarding the preprocessed data without scrubbing, the number of rs-fMRI measurements was either 180 or 128 depending on the data collection site. We discarded some of the later scans from the 180-scan data and analyzed the first 128 scans for all participants.We obtained whole-brain functional connectivity maps of the left and right thalamic seed regions using the Data Processing & Analysis of Brain Imaging (DPABI) tool [33] and the Automated Anatomical Labeling atlas [34], which was resampled to the space of functional images.

Data analysis

Between-group differences in descriptive statistics were examined using the Student’s t-test and chi-squared or Fisher’s exact test for continuous and categorical variables, respectively. Statistical tests were performed using SPSS (version 25.0; IBM, Armonk, NY), and the results were reported with a significance threshold of uncorrected p < 0.05.We compared thalamic functional connectivity maps between ADHD marijuana users and non-users. We set the cluster-forming height threshold at p < 0.001 uncorrected, and we used a family-wise error (FWE)-corrected cluster-defining threshold of p < 0.025, which was Bonferroni-adjusted (0.05/2) because we explored the left and right thalamic seeds separately. The analyses were performed using Statistical Parametric Mapping (SPM), which is based on MATLAB (MathWorks).

Results

Participant characteristics

The study participants included 18 cannabis users and 15 cannabis non-users with childhood ADHD. There was no significant difference in age, intelligence quotient, data collection site, handedness, ethnicity, or the proportion of smokers between the two groups (Table 1).

Between-group differences in functional connectivity

Compared with non-users, cannabis users showed a significant decrease in functional connectivity between the thalamus and the parietal regions in particular, which was particularly prominent in the inferior parietal areas, including the supramarginal gyrus (Table 2, Fig 1). These findings were largely consistent across the different preprocessing strategies. There was greater functional connectivity between the thalamus and the cuneus and calcarine gyrus in cannabis users than in non-users, which was not replicated across different sets of preprocessed data (Table 2).

Fig 1. Significant increase in thalamic functional connectivity in adult cannabis non-users with a childhood diagnosis of ADHD compared with their counterparts who were cannabis users.

(A) Scrubbing (+), global signal regression (+); (B) scrubbing (−), global signal regression (+), and (C) scrubbing (−), global signal regression (−). Results are displayed at a family-wise error-corrected cluster-defining threshold of p < 0.025.

https://doi.org/10.1371/journal.pone.0278162.g001

Table 2. Regional differences in thalamic functional connectivity between adult cannabis users and non-users, with childhood ADHD.

https://doi.org/10.1371/journal.pone.0278162.t002

Additional tests on the direction of change in functional connectivity

To explore whether the observed between-group difference was due to a decrease in connectivity among cannabis users or to an increase in connectivity among cannabis non-users, we performed additional analyses to compare their thalamic functional connectivity with that in the LNCG without childhood ADHD who were cannabis non-users (n = 7). There were no significant differences in descriptive parameters between the three groups, except in the proportion of smokers between ADHD cannabis users and non-users in the LNCG (S1 Table). We found significantly increased functional connectivity between the left thalamus and brain regions that encompassed the inferior parietal and middle frontal areas and significantly increased functional connectivity between the right thalamus and brain regions encompassing the inferior parietal and superior frontal areas in non-users with ADHD compared with those in the LNCG (Table 3, Fig 2). There was no significant decrease in thalamic connectivity in ADHD cannabis non-users and no significant difference in thalamic connectivity between ADHD cannabis users and the LNCG.

Fig 2. Significant increase in thalamic functional connectivity in adult cannabis non-users with a childhood diagnosis of ADHD compared with cannabis non-users without a childhood diagnosis of ADHD.

(A) Scrubbing (+), global signal regression (−) and (B) scrubbing (−), global signal regression (−). Results are displayed at a family-wise error-corrected cluster-defining threshold of p < 0.025.

https://doi.org/10.1371/journal.pone.0278162.g002

Table 3. Regional differences in thalamic functional connectivity among adult cannabis non-users, with and without childhood ADHD.

https://doi.org/10.1371/journal.pone.0278162.t003

Discussion

We found increased resting-state functional connectivity between the thalamus and the inferior and superior parietal cortices in particular as well as the superior and middle frontal cortices in adult cannabis non-users with a childhood diagnosis of ADHD.

The thalamus has been hypothesized to contribute to an increased addiction risk by enhancing responses to salient drug cues and attenuating the ability to inhibit these responses [21]. Salience processing refers to the identification of important external and/or interoceptive stimuli. The anterior insula and anterior midcingulate cortex are the central components of the brain’s salience network, and distributed brain regions, including the inferior parietal cortex and basal ventromedial nucleus of the thalamus, also participate in this large-scale brain network [35,36]. Our present findings of increased resting-state functional connectivity between the thalamus and inferior parietal cortex in cannabis non-users may thus be regarded in the context of salience processing toward drug cues. However, the inferior parietal lobe is also a convergence zone for different mental abilities, including language, attention, mathematical calculation, and social cognition [37]. Furthermore, long-term heavy cannabis use is associated with impaired working memory [38], which may be related to damage to the superior parietal cortex [39]. In one study, even after prolonged abstinence, brain processing efforts were greater in cannabis users than in non-users during inhibitory control, as evidenced by an increased blood-oxygen-level-dependent response in the frontal cortex as well as inferior and superior parietal cortices [40]. In summary, the increased thalamoparietal connectivity observed in cannabis non-users may reflect a better ability to control impulsive responses to drug cues [41], which would in turn facilitate more appropriate attribution of salience to behaviorally relevant stimuli other than cannabis (Table 4).

Table 4. Summary of findings and possible implications.

https://doi.org/10.1371/journal.pone.0278162.t004

The increased thalamoparietal connectivity in cannabis non-users with childhood ADHD was not only evident in the comparison with regular users of cannabis who had been diagnosed with ADHD but also in the comparison with the LNCG. Moreover, cannabis non-users with childhood ADHD showed increased thalamofrontal connectivity. The thalamus appears to mediate inhibitory control via its connectivity with the prefrontal cortex [42], and age-related progressive strengthening of thalamofrontal functional connectivity was observed in a sample of healthy children and adults [43]. Although patients with ADHD do not generally outgrow the disorder by adulthood, intermittent periods of remission can be expected in most cases [44]. Moreover, there has been a study showing that functional connectivity in the brains of adults whose inattentive symptoms had resolved did not differ significantly from that of their never-affected peers [45]. Therefore, adults who do not regularly use cannabis but have a past history of ADHD perhaps constitute a subgroup that provisionally attains relatively better thalamofrontal and thalamoparietal function, which can help inhibit responses to drug cues and thus reduce the frequency of cannabis use (Table 4).Other brain regions that show reduced functional connectivity with the thalamus in cannabis users have also been implicated in addiction in the literature. Cannabis users demonstrated significantly less activation of the precentral and postcentral regions during a finger-sequencing task compared with non-users [46,47]. Furthermore, the persistence of ADHD was associated with smaller precentral and postcentral cortical thickness, while the early onset of cannabis use in patients with ADHD was associated with greater postcentral cortical thickness [48]. Altered activation of the primary somatosensory cortex was associated with risky decision-making in patients with substance use disorder [49]. We found large symmetric differences in thalamic connectivity in both hemispheres, which is consistent with the almost exact mirror symmetry of resting-state connectivity between the thalamus and cortex in healthy young adults [50].Using the ACPI MTA data, Kelly and colleagues reported significant main effects of cannabis use history in two out of the nine large-scale intrinsic connectivity networks: the right superior temporal sulcus within the default network and the left fusiform gyrus within the lateral visual network both exhibited stronger intrinsic functional connectivity in cannabis users relative to non-users [29]. The nine large-scale intrinsic connectivity networks examined in this report included one network predominantly involving subcortical regions such as the amygdala, putamen, and thalamus; however, no significant findings were observed in the analysis using the predominantly subcortical network. The present work differs from that of Kelly and colleagues in that we specifically focused on the functional connectivity of the thalamus, based on a seed-to-whole brain approach using the thalamus as the seed, and found significant difference in thalamic connectivity between ADHD cannabis users and non-users. To further explore whether this difference was due to a decrease in connectivity among cannabis users or to an increase in connectivity among cannabis non-users, we performed additional analyses to compare their thalamic functional connectivity with that in the LNCG without childhood ADHD who were cannabis non-users. The only difference found in these subsequent analyses was increased bilateral thalamic functional connectivity in non-users with ADHD, and no significant difference in thalamic connectivity was observed between ADHD cannabis users and the LNCG. Albeit with different methods, Kelly and colleagues also did not observe a decrease in connectivity among cannabis users within the nine large-scale intrinsic connectivity networks tested, which is in line with the interpretation of our findings as an increase in connectivity among ADHD cannabis non-users rather than a decrease in connectivity among ADHD cannabis users.This study has several limitations. In the original MTA, four different treatments were randomly assigned to children with ADHD. However, no information was available on which participant received which treatment, whether the participant continued treatment during a period of extended follow-up, or the presence or absence of ADHD at the time of scanning. For example, it would also be interesting to examine whether thalamocortical connectivity displays any variations according to the level of compliance with medication. In addition, no information was available on the type of stimulant medication used for each participant (e.g., methylphenidate or dextroamphetamine) in the ACPI database. Moreover, behavioral measures of ADHD symptoms and cannabis use were not included in the dataset. Therefore, we were not able to explore the functional implications of altered thalamocortical connectivity. Considering that the original MTA collected a comprehensive set of clinical information, integrating those data into the ACPI database would help further research. In particular, more information is needed about cannabis use, such as the type of cannabis used, route of administration, as well as date of last use. For example, we were not able to verify if any participant had recently consumed cannabis before imaging acquisition, which is an important limitation considering that cannabinoids may affect brain functioning for 28 days after last use [51]. In addition, information about cannabis use was collected based on self-report, limiting data reliability. Moreover, no information was available on other psychiatric or substance use disorders in the ACPI database. Considering that ADHD is frequently comorbid with other mental disorders, absence of such information is an important limitation of this study. Finally, the sample size was small, and we only included men in our analysis because of the small number of women, which limits the generalizability of our findings. However, it is noteworthy that a high male predominance is among the typical characteristics of the population of interest [1,30]. The exclusion of participants with excessive head motion resulted in a further reduction of the study sample size, but may also contribute to the strength of the study. As the current study was based on an existing dataset, we were unable to alter the sample size, and despite the small sample size, we considered that the ACPI dataset was worthy of research as it contains unique data collected over a long time frame that would allow investigation of the link between prior childhood ADHD and later marijuana use in adulthood. Notably, despite the small sample size, our findings were observed at a relatively strong statistical significance level in terms of cluster size and p-value. Many of the findings survived a stringent Bonferroni correction for two thalamic seeds tested as well as four different preprocessing pipelines (p < 0.00625; 0.05/8). We expect that the current findings will provide an initial basis for further studies with a larger collection of data.

Conclusion

In conclusion, adults with a childhood diagnosis of ADHD who did not frequently use cannabis showed increased thalamoparietal connectivity compared with those who had ADHD in childhood and were regular users of cannabis. The increased thalamoparietal connectivity was replicated and increased thalamofrontal connectivity was observed in comparison with their peers who were cannabis non-users without a history of childhood ADHD. These findings support the hypothesis that the thalamus may be involved in cannabis use, at least in individuals with a past history of ADHD. Considering that individuals with ADHD are at a higher risk for other substance use, it would be interesting to examine if the implications of thalamic connectivity reported herein extend to other substance use. In addition, it would be interesting to examine if improvement in ADHD symptoms renders some protective effect against addiction, and whether an increase in thalamoparietal and/or thalamofrontal connectivity plays a role in this protective effect. Further studies are needed to examine thalamocortical connectivity in a larger sample of participants with ADHD and/or substance use disorder and its functional implications in response inhibition and salience to drug cues.

Introduction

Attention-deficit/hyperactivity disorder, known as ADHD, is a condition affecting brain development. It is marked by difficulties with attention, overactivity, and impulsive actions. ADHD is a common mental health condition among children, affecting about 5% of this population. For up to 65% of individuals, symptoms of ADHD continue into adulthood, leading to ongoing challenges in social and personal functioning.

Individuals with ADHD often exhibit a heightened tendency for reward-seeking behaviors and face an increased risk of developing substance use disorders. It has been observed that approximately 23% of those with a substance use disorder also have ADHD. Cannabis is widely used, particularly among adolescents and young adults. Studies indicate that children with ADHD are significantly more likely to use cannabis and to become dependent on it compared to those without ADHD. For example, some analyses show that individuals diagnosed with ADHD in childhood have nearly three times higher odds of lifetime cannabis use and a 1.5 times greater likelihood of developing cannabis use disorder in young adulthood.

The thalamus, a brain structure, is a crucial part of a circuit involved in brain function, and problems within this circuit have been linked to ADHD. Research on brain volume in young children with ADHD has shown reductions in subcortical areas, including the thalamus, though this finding has not always been consistent in older children. Other studies have found reduced brain activity, including in the thalamus, in adults with a childhood ADHD diagnosis during tasks requiring self-control and flexible thinking, which may be connected to substance use disorders. Additionally, brain connectivity patterns involving the thalamus have shown differences in children with ADHD.

The thalamus is thought to play a significant role in addiction, especially by affecting how individuals control their impulses and respond to drug-related cues. For instance, altered thalamic connectivity has been observed in individuals who smoke, those in recovery from alcohol addiction, and young adults with untreated cannabis use disorder. Volume reductions in the thalamus have also been reported in users of synthetic cannabinoids. Furthermore, a common ADHD medication, methylphenidate, can affect thalamic connectivity, but this effect appears blunted in individuals with cannabis use disorder.

Based on these observations, both ADHD and cannabis use may be related to the resting-state functional connectivity of the thalamus. However, there is limited understanding of how thalamic connectivity contributes to the increased risk of cannabis use in individuals with ADHD. This study aimed to investigate the brain-based relationship between ADHD and cannabis use, focusing specifically on the thalamus. The hypothesis was that thalamic connectivity would be lower in cannabis users who had been diagnosed with ADHD in childhood. The study examined resting-state functional thalamic connectivity in adults with a childhood ADHD diagnosis, based on their current cannabis use.

Study Design and Participants

This research utilized data from the Multimodal Treatment Study of ADHD (MTA), a long-term study initially funded by the National Institute of Mental Health. The analysis specifically used resting-state functional magnetic resonance imaging (rs-fMRI) data from the Addiction Connectome Preprocessed Initiative (ACPI) MTA database. This public database contains MRI scans and detailed participant information, including age, sex, intelligence, data collection site, handedness, ethnicity, education level, smoking status, current ADHD medication use, and group assignments for ADHD and marijuana use. Information on other factors, such as anxiety, depression, or use of other substances, was not available in this dataset.

Participants in the original MTA study met diagnostic criteria for ADHD combined type, based on established clinical interviews and parent/teacher reports. A control group, known as the local normative comparison group (LNCG), was also included, consisting of age- and sex-matched classmates without ADHD. For this study, 129 participants from the ACPI dataset were categorized into four groups: ADHD cannabis users, ADHD cannabis non-users, LNCG cannabis users, and LNCG cannabis non-users. Cannabis users were defined as those who used cannabis at least once per month, while non-users reported using cannabis fewer than four times in the past year, based on self-reported surveys. Due to a significant imbalance in the male-to-female ratio across groups, which could have influenced the findings, only male participants were included in the primary analysis. Informed consent was obtained from all families in the original MTA study. This study, using de-identified data, was exempted from review by the Institutional Review Board at the Seoul National University Hospital.

Image Processing

The study used rs-fMRI data that had been preprocessed using Advanced Normalization Tools (ANTs) software and made available by the ACPI. To ensure the reliability of the findings, all four versions of the preprocessed datasets provided by ACPI, which vary by motion correction and nuisance correction methods, were used in the analysis. Detailed steps of the processing pipeline are publicly documented.

To address the issue of head motion during scanning, which can significantly affect rs-fMRI studies, participants with fewer than 100 usable scans after motion correction (scrubbing) were excluded. This exclusion resulted in reduced sample sizes for each group. Given the study's focus on thalamic connectivity in relation to cannabis use among individuals with ADHD, the main comparison was made between ADHD cannabis users and non-users. The decision to focus solely on male participants was further reinforced by the very small number of female participants remaining after the motion correction exclusion, which would have led to severe sex imbalances across groups. For datasets without scrubbing, the first 128 scans were analyzed for all participants to standardize data length. Whole-brain functional connectivity maps for the left and right thalamic regions were generated using specific brain imaging analysis tools and an anatomical atlas.

Data Analysis

Statistical comparisons of demographic characteristics between groups were performed using standard statistical tests for continuous and categorical variables. A significance threshold was set.

Thalamic functional connectivity maps were compared between ADHD cannabis users and non-users. A specific cluster-forming height threshold was applied, along with a family-wise error-corrected cluster-defining threshold, which was adjusted to account for testing both left and right thalamic regions separately. The analyses were conducted using statistical software based on MATLAB.

Participant Characteristics

The study included 18 male cannabis users and 15 male cannabis non-users, all of whom had a childhood diagnosis of ADHD. No significant differences were found between these two groups regarding age, intelligence quotient, data collection site, handedness, ethnicity, or the proportion of smokers.

Between-Group Differences in Functional Connectivity

When comparing cannabis users to non-users, individuals with a childhood diagnosis of ADHD who used cannabis showed a notable decrease in functional connectivity between the thalamus and regions in the parietal lobe, particularly in the inferior parietal areas such as the supramarginal gyrus. These findings were largely consistent across the various preprocessing strategies used in the analysis. A finding of greater functional connectivity between the thalamus and the cuneus and calcarine gyrus in cannabis users compared to non-users was also observed, but this was not consistently replicated across all preprocessing methods.

Additional Tests on the Direction of Change in Functional Connectivity

To further understand whether the observed differences were due to decreased connectivity in cannabis users or increased connectivity in cannabis non-users, additional analyses were conducted. Thalamic functional connectivity was compared among three groups: ADHD cannabis users, ADHD cannabis non-users, and a control group of cannabis non-users without childhood ADHD (LNCG). No significant differences in descriptive characteristics were found among these three groups, except for the proportion of smokers between ADHD cannabis users and LNCG non-users.

The analysis revealed significantly increased functional connectivity between the left thalamus and brain regions encompassing the inferior parietal and middle frontal areas in ADHD cannabis non-users. Similarly, increased functional connectivity was found between the right thalamus and brain regions covering the inferior parietal and superior frontal areas in ADHD cannabis non-users, when compared to the LNCG. Importantly, no significant decrease in thalamic connectivity was observed in ADHD cannabis non-users, nor was there a significant difference in thalamic connectivity between ADHD cannabis users and the LNCG.

Discussion

This study observed increased resting-state functional connectivity between the thalamus and specific brain regions, including the inferior and superior parietal cortices, and the superior and middle frontal cortices, in adults with a childhood diagnosis of ADHD who did not use cannabis regularly.

The thalamus has been theorized to contribute to a higher risk of addiction by enhancing responses to drug cues and reducing the ability to control these responses. The brain's salience network, which identifies important internal and external stimuli, includes the inferior parietal cortex and parts of the thalamus. The finding of increased resting-state functional connectivity between the thalamus and inferior parietal cortex in cannabis non-users might suggest better salience processing, potentially relating to responses to drug cues. The inferior parietal lobe is also crucial for various mental abilities, including attention and cognition. Furthermore, previous research indicates that long-term cannabis use can impair working memory, possibly linked to damage in the superior parietal cortex. Increased thalamoparietal connectivity in cannabis non-users may therefore indicate a better capacity to control impulsive reactions to drug cues, which could lead to more appropriate attention to stimuli other than cannabis.

The increased thalamoparietal connectivity in cannabis non-users with childhood ADHD was evident not only when compared to regular cannabis users with ADHD but also when compared to the control group without childhood ADHD who did not use cannabis. Additionally, cannabis non-users with childhood ADHD showed increased connectivity between the thalamus and frontal brain regions. The thalamus is believed to facilitate inhibitory control through its connections with the prefrontal cortex, and a strengthening of thalamofrontal connectivity is observed with age in healthy individuals. While ADHD symptoms can persist into adulthood, periods of remission are possible for many. Some studies suggest that the brain connectivity of adults whose inattentive ADHD symptoms have resolved may not differ significantly from those who never had ADHD. Therefore, adults with a history of childhood ADHD who do not regularly use cannabis might represent a subgroup that has achieved relatively better thalamofrontal and thalamoparietal function. This improved function could help inhibit responses to drug cues and consequently reduce the frequency of cannabis use.

Other brain areas showing reduced functional connectivity with the thalamus in cannabis users have also been implicated in addiction. For example, cannabis users have shown less activation in certain brain regions during motor tasks. The persistence of ADHD has been associated with thinner brain cortices in some areas, while early cannabis use in individuals with ADHD has been linked to thicker cortices in others. Altered activity in the primary somatosensory cortex has also been associated with risky decision-making in individuals with substance use disorder. The study observed similar patterns of changes in thalamic connectivity in both brain hemispheres. While other studies using the same dataset did not find significant findings in a subcortical network that included the thalamus, this current research specifically focused on thalamic connectivity using a seed-to-whole brain approach, revealing significant differences between ADHD cannabis users and non-users. This supports the interpretation that the observed difference is an increase in connectivity among ADHD cannabis non-users, rather than a decrease among ADHD cannabis users.

This study has several limitations. Information on specific ADHD treatments, the continuity of treatment, or current ADHD symptom status at the time of scanning was not available. For example, it would be beneficial to know if medication adherence affects thalamocortical connectivity. Details about the type of stimulant medication were also unavailable. Furthermore, the dataset lacked behavioral measures of ADHD symptoms and precise cannabis use patterns, such as type, administration route, or date of last use, which could impact brain function. Cannabis use information was self-reported, potentially affecting data reliability. The absence of information on other psychiatric or substance use disorders is also a limitation, given the common co-occurrence of ADHD with other conditions. Finally, the sample size was small, and only male participants were included due to the limited number of women, which affects the generalizability of the findings. However, the study's focus on a population with a known male predominance somewhat mitigates this. Despite the small sample, the study utilized a unique long-term dataset and achieved strong statistical significance in its findings, which are expected to provide a foundation for future larger studies.

Conclusion

Adults with a childhood diagnosis of ADHD who did not frequently use cannabis showed increased connectivity between the thalamus and parietal brain regions compared to those with childhood ADHD who regularly used cannabis. This increased thalamoparietal connectivity was also observed when compared to individuals without a history of childhood ADHD who did not use cannabis. Additionally, increased connectivity between the thalamus and frontal brain regions was noted in ADHD cannabis non-users. These findings suggest that the thalamus plays a role in cannabis use, especially in individuals with a history of ADHD. Given that individuals with ADHD face a higher risk for other substance use, future research could explore if these implications of thalamic connectivity extend to other substances. It would also be valuable to investigate whether improvements in ADHD symptoms offer protection against addiction, and if increased thalamoparietal and/or thalamofrontal connectivity contributes to this protective effect. Further studies with larger participant groups are needed to examine thalamocortical connectivity in individuals with ADHD and/or substance use disorder and its functional relevance to response inhibition and sensitivity to drug cues.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a brain-based condition marked by challenges with inattention, hyperactivity, and impulsivity. It is a common mental health condition in children, affecting about 5% of this age group. For many individuals, symptoms of ADHD continue into adulthood, impacting various aspects of life over time. People with ADHD often seek rewards more intensely and face a higher risk of developing substance use disorder. In fact, roughly 23% of individuals with substance use disorder also have ADHD. Cannabis is a widely used substance, with high rates of use among adolescents and young adults. Studies indicate that children with ADHD are significantly more likely to use cannabis and become dependent on it compared to those without ADHD.

The thalamus, a key brain region, is part of a circuit linked to ADHD. Research suggests differences in brain activity and structure involving the thalamus in individuals with ADHD. The thalamus may also play an important role in addiction, particularly in managing impulses and reacting to drug-related cues. Previous studies have observed changes in thalamic connectivity in individuals who use substances like cannabis. Given that both ADHD and cannabis use are associated with thalamic connectivity, this study aimed to investigate the relationship between ADHD and cannabis use, focusing specifically on the thalamus. It was hypothesized that thalamic connectivity would be reduced in cannabis users who had received a childhood diagnosis of ADHD.

Methods

Study design and participants

This study analyzed data from the Multimodal Treatment Study of ADHD (MTA), a long-term research project. The data, including functional magnetic resonance imaging (fMRI) scans and demographic information, was obtained from a public database. Participants were originally classified based on their childhood ADHD diagnosis and later on their marijuana use. Four groups were identified: ADHD marijuana users, ADHD marijuana non-users, non-ADHD marijuana users, and non-ADHD marijuana non-users. To avoid potential biases from gender differences, only male participants were included in the final analysis, as there was a significant imbalance in the male-to-female ratio across the groups. Information about other conditions or specific treatment details from the original study was not available in the public dataset. All participants provided informed consent for the original MTA study. The current analysis used de-identified data and was exempt from further institutional review.

Image processing

The study utilized preprocessed resting-state fMRI data. To ensure the reliability of the findings, all four versions of the preprocessed datasets were used, which differed in how motion correction and nuisance correction were applied. Participants with excessive head motion, defined as fewer than 100 usable scans after motion correction, were excluded. This exclusion led to a smaller sample size, particularly limiting the number of female participants and reinforcing the decision to focus solely on male participants for the main analysis. For data without scrubbing, the initial 128 scans were analyzed consistently across all participants. Whole-brain functional connectivity maps were generated for both the left and right thalamic regions.

Data analysis

Statistical comparisons of participant characteristics between groups, such as age and intelligence, were conducted using standard statistical tests. A significance level was set to identify differences. The primary analysis compared thalamic functional connectivity maps between individuals with childhood ADHD who used cannabis and those who did not. A strict statistical threshold was applied to identify significant brain regions, with separate analyses for the left and right thalamus. These analyses were performed using specialized software.

Results

Participant characteristics

The study included 18 cannabis users and 15 cannabis non-users, all of whom had a childhood diagnosis of ADHD. There were no significant differences between these two groups in terms of age, intelligence, data collection site, handedness, ethnicity, or the proportion of smokers.

Between-group differences in functional connectivity

Compared to those who did not use cannabis, individuals with ADHD who used cannabis showed significantly reduced functional connectivity between the thalamus and regions in the parietal lobe, especially the inferior parietal areas. These findings remained largely consistent even when different preprocessing methods for the brain imaging data were used. While there was also some indication of increased connectivity between the thalamus and certain visual processing areas in cannabis users, this finding was not consistently observed across all data preprocessing strategies.

Additional tests on the direction of change in functional connectivity

To better understand whether the observed differences were due to decreased connectivity in cannabis users or increased connectivity in cannabis non-users, additional comparisons were made. Thalamic functional connectivity in ADHD cannabis non-users was compared with that in a control group of cannabis non-users who did not have a childhood ADHD diagnosis. This analysis revealed significantly increased functional connectivity between the left thalamus and areas of the inferior parietal and middle frontal regions in ADHD cannabis non-users. Similarly, increased connectivity was found between the right thalamus and parts of the inferior parietal and superior frontal regions in this group. No significant decrease in thalamic connectivity was found in ADHD cannabis non-users, nor was there a significant difference in thalamic connectivity between ADHD cannabis users and the control group without ADHD.

Discussion

This study revealed increased resting-state functional connectivity between the thalamus and specific brain regions, including the inferior and superior parietal cortices, as well as the superior and middle frontal cortices, in adults who had a childhood ADHD diagnosis but did not regularly use cannabis.

The thalamus is believed to contribute to a higher risk of addiction by strengthening responses to drug cues and weakening the ability to resist these responses. The inferior parietal cortex and parts of the thalamus are involved in the brain's salience network, which identifies important stimuli. Therefore, the observed increased functional connectivity between the thalamus and the inferior parietal cortex in cannabis non-users might relate to how they process drug cues. The inferior parietal lobe also plays a role in various mental abilities, including attention and cognitive control. Stronger thalamoparietal connectivity in cannabis non-users may indicate a better capacity to control impulsive reactions to drug cues, allowing for more appropriate responses to other relevant stimuli instead of cannabis.

The increased thalamoparietal connectivity in cannabis non-users with childhood ADHD was evident not only when compared to regular cannabis users with ADHD but also when compared to individuals without a childhood ADHD diagnosis. Additionally, cannabis non-users with childhood ADHD showed increased connectivity between the thalamus and the frontal lobe. The thalamus appears to help mediate inhibitory control through its connections with the prefrontal cortex. While ADHD often persists into adulthood, some individuals experience periods of symptom improvement. It is possible that adults with a history of ADHD who do not regularly use cannabis represent a subgroup that has developed better thalamofrontal and thalamoparietal function, which could help them inhibit responses to drug cues and reduce cannabis use.

Other brain regions showing reduced functional connectivity with the thalamus in cannabis users have also been linked to addiction in previous research. Altered activity in certain brain areas is associated with risky decision-making in individuals with substance use disorder. This study's findings of large, symmetrical differences in thalamic connectivity align with the generally symmetrical connectivity between the thalamus and cortex in healthy adults. This work specifically focused on thalamic connectivity, differentiating its approach from previous studies that examined broader brain networks. The results suggest that the difference observed is due to increased connectivity in ADHD cannabis non-users rather than a decrease in connectivity in ADHD cannabis users.

This study has several limitations. Information regarding specific ADHD treatments, their continuation, or the persistence of ADHD symptoms at the time of scanning was not available. More detailed information about cannabis use, such as type, administration route, and recency of use, would have enhanced the study, especially since cannabinoids can affect brain function for an extended period after use. Data on cannabis use was based on self-report, which can affect reliability. Furthermore, the dataset lacked information on other co-occurring psychiatric or substance use disorders, which are common with ADHD. Finally, the sample size was small, and the analysis was limited to male participants due to an insufficient number of female participants, which restricts the generalizability of the findings. Despite these limitations, the dataset offered unique longitudinal data on childhood ADHD and later marijuana use, and the observed findings reached strong statistical significance.

Conclusion

Adults diagnosed with ADHD in childhood who were not regular cannabis users showed increased connectivity between the thalamus and parietal brain regions compared to those with a childhood ADHD diagnosis who were regular cannabis users. This increased thalamoparietal connectivity, along with observed increases in thalamofrontal connectivity, was also evident when comparing ADHD cannabis non-users to individuals without a childhood ADHD diagnosis who did not use cannabis. These findings support the idea that the thalamus plays a role in cannabis use, especially in individuals with a history of ADHD. Given that individuals with ADHD are at a higher risk for other substance use, future research could explore whether these implications of thalamic connectivity extend to other substances. It would also be valuable to investigate if improvements in ADHD symptoms offer protection against addiction, and whether enhanced thalamoparietal and/or thalamofrontal connectivity contributes to such a protective effect. Further studies with larger participant groups are needed to fully understand thalamocortical connectivity in ADHD and substance use disorder, and its functional impact on impulse control and responses to drug cues.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a brain-based condition marked by problems with focus, being overly active, and acting on impulse. It is commonly diagnosed in children, and for many, these symptoms continue into adulthood. Adults with ADHD often face ongoing challenges in their daily lives.

Individuals with ADHD tend to seek out rewards more often and have a higher chance of developing substance use disorders. About one-quarter of people with substance use disorder also have ADHD. Cannabis is a widely used substance, especially among young adults. Research shows that children diagnosed with ADHD are significantly more likely to use marijuana and become dependent on it later in life compared to those without ADHD.

The thalamus, a part of the brain, is thought to be involved in ADHD, as disruptions in brain circuits connected to it have been noted. This area of the brain may also play a role in addiction, particularly in how people respond to drug-related cues and control their impulses. This study aimed to explore the connection between ADHD and cannabis use by looking at the thalamus's brain activity. It was expected that individuals with ADHD who use cannabis would show less activity in their thalamus compared to those with ADHD who do not use cannabis.

Methods

This study analyzed brain imaging data from a long-term research project called the Multimodal Treatment Study of ADHD (MTA). The data, including brain scans and information like age and sex, was publicly available. The original MTA study included children diagnosed with ADHD and a comparison group of classmates who did not have ADHD.

For this study, researchers looked at brain imaging from 129 participants, dividing them into four groups: ADHD cannabis users, ADHD cannabis non-users, a comparison group of cannabis users, and a comparison group of cannabis non-users. Individuals were considered cannabis users if they used it at least once a month, and non-users if they used it fewer than four times in the past year. Because there were many more males than females in the study, and to avoid issues with gender imbalances, only male participants were included in the final analysis. All participants had given their consent for the original study.

The brain scan data had already been prepared for analysis using specialized software. To ensure the results were reliable, researchers used four different versions of the processed data. Participants with too much head movement during scanning were excluded, which led to a smaller sample size for analysis. The study focused on comparing brain activity related to the thalamus between the ADHD cannabis users and non-users. Statistical tests were used to find significant differences in brain connectivity between these groups.

Results

The study included 18 cannabis users and 15 cannabis non-users, all of whom had been diagnosed with ADHD in childhood. There were no major differences between these two groups in terms of age, intelligence, location where data was collected, or whether they smoked.

Compared to those with ADHD who did not use cannabis, the cannabis users showed notably less brain activity connecting the thalamus to areas in the parietal regions of the brain. These differences were consistent across the different ways the data was processed. There were some minor findings of greater connectivity in cannabis users in other brain areas, but these were not as consistently found across all data sets.

To understand if the differences were due to decreased activity in cannabis users or increased activity in non-users, additional comparisons were made. Researchers compared the ADHD cannabis users and non-users to a smaller group of individuals from the comparison group who did not have ADHD and did not use cannabis. These additional tests revealed that the ADHD cannabis non-users had significantly increased brain activity between the left thalamus and certain frontal and parietal brain regions, and similarly increased activity between the right thalamus and other frontal and parietal areas, compared to the non-ADHD, non-cannabis users. No significant decrease in thalamus activity was found in ADHD cannabis non-users. Also, there was no significant difference in thalamus activity between ADHD cannabis users and the non-ADHD, non-cannabis users.

Discussion

The study found increased brain activity connecting the thalamus with specific areas in the parietal and frontal parts of the brain in adults with a childhood ADHD diagnosis who did not use cannabis regularly.

The thalamus is believed to contribute to addiction risk by making drug-related cues more noticeable and by weakening the ability to resist these cues. The increased brain activity seen in non-users might suggest a better ability to manage impulses related to drug cues. This could mean these individuals are better at focusing on other important things in their environment instead of cannabis. The frontal areas of the brain are also involved in controlling impulses, and their connection to the thalamus appears to strengthen with age in healthy individuals.

It is known that ADHD symptoms can lessen or resolve in adulthood for some individuals. Therefore, adults with a history of ADHD who do not use cannabis frequently might represent a group that has achieved better brain function in areas like the thalamus and its connections to the frontal and parietal regions. This improved brain function could help them resist drug cues and reduce their cannabis use. Other studies have also linked altered brain activity in cannabis users to problems with decision-making and motor control.

Conclusion

Adults with a childhood ADHD diagnosis who did not frequently use cannabis showed increased brain activity connecting their thalamus to the parietal areas of their brain, compared to those with ADHD who regularly used cannabis. This increased brain activity was also observed in comparison to individuals without ADHD who did not use cannabis. These findings suggest that the thalamus may play a role in cannabis use, especially for those with a history of ADHD. Further research with more participants is needed to understand the specific impact of thalamus connections on controlling impulses and responding to drug-related cues in individuals with ADHD and substance use disorders.

Introduction

Attention-deficit/hyperactivity disorder, known as ADHD, is a difference in the brain that can cause trouble focusing, being overly active, and acting without thinking. It is one of the most common brain differences found in children. For many people, symptoms of ADHD continue into adulthood, leading to challenges in daily life.

People with ADHD tend to seek out rewards more often and are at a higher risk of developing a substance use disorder, which means they might struggle with addiction. About a quarter of people with substance use disorder also have ADHD. Marijuana is one of the most commonly used substances, especially among young people. Studies have shown that children with ADHD are much more likely to use marijuana and become dependent on it later in life compared to those without ADHD.

The thalamus is a key part of the brain that helps different brain areas talk to each other. Problems with these brain connections have been linked to ADHD. Previous studies have shown that adults who had ADHD as children might have less brain activity in the thalamus during tasks that require them to stop unwanted actions or change their thinking. These changes might be connected to substance use disorder.

Studies also show that the thalamus might play an important role in addiction, especially in making people less able to stop urges and more focused on drug-related things. It is known that brain connections involving the thalamus can be different in people who use substances like marijuana. This study looked at how the thalamus connects to other brain parts in adults who had ADHD as children, focusing on whether they used marijuana. The study expected that connections in the thalamus would be weaker in marijuana users with a history of ADHD.

Methods

Study design and participants

This study used brain scan data from a long-term research project called the Multimodal Treatment Study of ADHD (MTA). This data, along with basic health information, was made public for other researchers to use. The original MTA study included children diagnosed with ADHD based on standard medical guidelines. It also included a group of children without ADHD, who were similar in age and sex, to compare with.

For this specific study, 129 people were grouped based on whether they had ADHD as a child and whether they used marijuana. Marijuana users were defined as those who used marijuana at least once a month, while non-users used it fewer than four times in the past year. Because there were more males in the study who had ADHD and used marijuana, and to make sure the groups were balanced, only male participants were included in the main analysis. All families in the original MTA study gave written permission for their information to be used. This study used private, deidentified data, meaning no one's identity was known.

Image processing

The brain scans, called fMRI data, had been prepared using special computer tools. These tools helped clean up the data, for example, by correcting for small head movements during the scan, which can make results unclear. To ensure accurate results, participants who moved too much during the scan were not included if their usable scan time was too short. This led to a smaller group of participants for the brain analysis. The study focused on how the left and right sides of the thalamus connected to all other parts of the brain.

Data analysis

Researchers looked at basic information about the groups, such as age and intelligence, to see if they were similar. They then compared the brain connection maps of the thalamus between adults with childhood ADHD who used marijuana and those who did not. They used special computer programs to find meaningful differences in brain connections.

Results

Participant characteristics

The study included 18 men with childhood ADHD who used marijuana and 15 men with childhood ADHD who did not use marijuana. The two groups were similar in age, intelligence, study location, and whether they smoked tobacco.

Between-group differences in functional connectivity

When comparing adults with childhood ADHD, those who used marijuana showed weaker connections between their thalamus and specific brain areas, especially in the parietal regions, which are near the top and back of the head. These findings were generally consistent even when the data was processed in slightly different ways. Sometimes, marijuana users also showed stronger connections between the thalamus and other areas, but these findings were not as consistent.

Additional tests on the direction of change in functional connectivity

To understand whether the differences were because connections decreased in marijuana users or increased in non-users, the researchers also compared the ADHD non-users to a group of men who never had ADHD and did not use marijuana. They found that adults with ADHD who did not use marijuana had significantly stronger connections between their thalamus and certain brain areas, including the frontal and parietal regions, compared to the group without ADHD. There was no big difference in thalamus connections between the ADHD marijuana users and the group without ADHD. This suggests that the stronger connections were a unique feature of the ADHD non-users.

Discussion

The study found that adults with a childhood diagnosis of ADHD who did not use marijuana frequently had stronger connections between their thalamus and the parietal and frontal parts of their brain. The thalamus has been thought to play a role in addiction by making people more likely to notice drug-related things and less able to stop acting on urges.

The parietal part of the brain helps with many mental skills, including attention. The stronger connections observed in the ADHD non-users might mean they are better at controlling their urges related to drugs. They might also be better at giving importance to things other than marijuana. This suggests that these stronger brain connections could help protect against marijuana use.

People with ADHD can experience times when their symptoms get better. It is possible that the adults in this study who had ADHD but did not use marijuana had reached a point where their brain was functioning better in these key areas. This improved function might help them resist drug cues and therefore use marijuana less often.

Other brain areas that showed weaker connections with the thalamus in marijuana users are also known to be involved in addiction. These differences were seen on both sides of the brain. This study's findings are similar to other research that suggests specific brain connections are important in how ADHD and substance use relate.

However, this study had some limitations. It did not have information on past ADHD treatments, if ADHD symptoms were still present during the scans, or details about other drug use or mental health conditions. The information about marijuana use was based on self-reports, which might not always be perfectly accurate. Also, the study had a small number of participants and only included men, so the findings might not apply to everyone. Despite these limits, the data came from a long-term study, which makes the findings valuable. The results were also very clear, showing that even with a smaller group, the differences in brain connections were real.

Conclusion

In summary, adults who had ADHD as children but did not regularly use marijuana showed stronger connections between their thalamus and the parietal and frontal areas of their brain. This was true when compared to adults with childhood ADHD who did use marijuana regularly, and also when compared to people who never had ADHD and did not use marijuana.

These findings support the idea that the thalamus and its connections may be important in understanding marijuana use, especially for people who have a history of ADHD. Given that people with ADHD are at a higher risk for other types of substance use, future studies should explore if these findings about thalamic connections also apply to other substances. It would also be helpful to see if improving ADHD symptoms leads to these stronger brain connections, and if those stronger connections help protect against addiction. More studies with larger groups of people are needed to further understand how the thalamus and its brain connections relate to ADHD and substance use.