This secondary analysis of an observational study (n=30) - named MISTIC - of Special Operations Forces veterans with blast-related traumatic brain injury, examined ibogaine given with magnesium and found increased cortical thickness, larger subcortical volumes and a lower estimated brain age one month later. The authors note that the MRI changes could reflect neuroplastic effects, although the scans may also be influenced by non-structural factors.
Ibogaine is a psychoactive alkaloid with therapeutic potential that may promote neuroplasticity. Its effects on human brain morphometry are unknown. Thirty Special Operations Forces veterans with prior blast-induced TBI participated in an observational study in which they received ibogaine co-administered with magnesium. Structural MRIs were collected at baseline (n = 25), initial post-treatment (n = 25), and 1-month post (n = 22). Longitudinal analyses assessed cortical thickness, subcortical volume, and predicted brain age (pBA), estimated from T1 scans. pBA was significantly reduced at 1 month relative to baseline (-1.3 years). Cortical thickness analysis revealed post-treatment increases in 11 regions. Subcortical analyses revealed significant volumetric expansion in 8 regions. Magnesium-ibogaine therapy was associated with increased cortical thickness, subcortical expansion, and reduced pBA at 1 month. Although T1s are sensitive to nonstructural changes, the overall direction of effect is consistent with neuroplastic change.
Traumatic brain injury (TBI), particularly blast-related TBI in military veterans, is a major and persistent health problem with few effective treatments. The paper describes blast TBI as a diffuse injury that can produce long-term disability, persistent post-concussion symptoms, psychiatric comorbidity, and possible accelerated brain ageing. The authors note that chronic TBI is often associated with white matter disruption, cortical thinning, and reduced brain volume, but it remains uncertain whether any rapid-acting intervention can reverse or modify these structural changes. Within that context, the paper considers ibogaine, a psychoactive compound of interest for psychiatric sequelae of TBI, including depression, anxiety, and addiction. The researchers state that a prior observational pilot study of a magnesium-ibogaine protocol in special operations veterans had already shown clinical improvements, and they hypothesised that these benefits might be accompanied by measurable changes in cortical thickness, subcortical volume, and predicted brain age on MRI. The study therefore aimed to examine whether structural brain changes could be detected after treatment and whether those changes tracked with the previously reported clinical response. The authors frame this as an early morphometric analysis of MRI data from a clinical treatment cohort, using longitudinal imaging and brain-age modelling to explore possible neurobiological correlates of the protocol.
This was an observational, longitudinal MRI analysis nested within a magnesium-ibogaine treatment protocol for special operations veterans with TBI and multiple comorbidities. Of the 30 treated participants, usable imaging data were available for 25 at baseline and the immediate post-treatment visit, and 22 had usable 1-month follow-up scans. All participants were male; the mean age was 44.5 years, and most had mild TBI, although one had moderate TBI and one had moderately severe TBI. The paper also reports a high lifetime TBI burden and combat exposure, but the extracted text does not clearly restate all inclusion and exclusion criteria. MRI data were acquired on a T1-weighted protocol at approximately the same time of day across visits. The authors processed the scans using the ANTs longitudinal pipeline to derive cortical thickness and log-jacobian determinant maps, and they also ran FreeSurfer longitudinal processing in parallel as a comparison. After pipeline evaluation, they selected ANTs for the formal analyses because it performed better on their dataset. Cortical thickness was quantified in 62 regions of interest, and volumetric change was assessed in 28 subcortical and cerebellar regions from the Mindboggle atlas. The researchers used linear mixed-effects models with study visit as the main fixed effect and covariates including chronological age, combat exposure score, number of TBIs, and estimated total intracranial volume, with a random intercept for participant. They first tested whole-brain average cortical thickness, then regional cortical thickness and volumetric change. Predicted brain age was estimated with the brainageR algorithm from structural MRI. Normative modelling was also used to compare cortical thickness percentile ranks with a normative reference framework. The authors additionally examined associations between imaging changes and clinical or neurocognitive outcomes, including WHODAS-2.0 and other measures, with correction for multiple testing.
The study found a statistically significant main effect of study visit on whole-brain average cortical thickness. Mean cortical thickness increased modestly from 2.08 mm at baseline to 2.13 mm immediately post-treatment and remained at 2.13 mm at 1 month. After multiple-comparison correction, pairwise contrasts were only trend-level for the global measure, but regionally the authors report significant visit effects in 13 of 62 cortical regions. Post-hoc tests showed significant increases from baseline to immediate post-treatment in 11 regions, and additional significant baseline-to-1-month increases in the right entorhinal cortex and right postcentral cortex. There were no significant changes between immediate post-treatment and 1 month, suggesting the increases were sustained rather than continuing to rise further. Normative modelling also showed significant visit-related change. Targeted normative percentile ranks increased by about 7.49 percentile points from baseline to immediate post-treatment and by 8.70 points from baseline to 1 month. For the whole-brain normative analysis, the increases were only trend-level. For subcortical and cerebellar volume, the authors report significant visit effects in 8 regions. Post-hoc analyses identified bilateral volumetric expansion in cerebellar white matter, basal forebrain, and ventral diencephalon, plus the right hippocampus, from baseline to immediate post-treatment. Some of these changes persisted at 1 month, particularly in the ventral diencephalon and left-sided cerebellar white matter and basal forebrain. The left caudate showed a significant contraction over time. No significant baseline-to-1-month increase was seen in the right hippocampus, indicating that the hippocampal expansion was transient. Predicted brain age decreased over time. Mean predicted brain age fell from 39.37 years at baseline to 38.54 years at 1 month, while mean chronological age was about 44.5 years. The mixed-effects model showed a significant visit effect on predicted brain age, and the only significant post-hoc comparison was between baseline and 1 month, corresponding to an estimated mean reduction of 1.3 years. Chronological age and grey matter signal-to-noise ratio were also significant covariates in the model. The exploratory analyses found no significant correlations between imaging changes and WHODAS-2.0 total score after correction. Likewise, most associations between morphometric change and psychiatric or neurocognitive measures did not survive false discovery rate correction. One association between baseline-to-1-month predicted brain age change and 1-month Hamilton Anxiety Rating Scale score normalised to baseline was mentioned, but a subsequent regression did not support a predictive relationship.
The authors interpret the findings as the first group-level evidence that a magnesium-ibogaine protocol may be associated with measurable structural brain changes in humans over one month. They argue that the combination of increased cortical thickness, subcortical volumetric expansion, and reduced predicted brain age may reflect structural neural plasticity and could be linked, at least indirectly, to the clinical improvements reported in their prior work. They also note that many of the cortical changes were right-lateralised, which they consider less likely to be purely artifactual than a more symmetric pattern would be. In relation to earlier research, the authors compare their findings with studies of blast TBI showing cortical thinning, as well as with other rapid-acting interventions such as electroconvulsive therapy and some antidepressant or behavioural interventions that have been associated with regional thickening or volume changes. They suggest that the thickening seen in regions previously reported to thin in military blast TBI may represent a possible reversal-like pattern. They also place the reduction in predicted brain age in the context of prior work showing changes in brain-age estimates after surgery, ibuprofen, and the postpartum period. The authors are cautious about interpretation. They emphasise that machine-learning brain-age measures should not be read literally as the brain becoming younger, but rather as images resembling younger normative patterns. They also note that longitudinal T1 changes may reflect non-structural factors such as tissue water content, so the biological meaning of the observed morphometric changes remains uncertain. For the caudate contraction, they discuss alternative interpretations, including possible changes in synaptic efficiency or network organisation, and argue that it should not automatically be viewed as harmful. Key limitations include the absence of a control group, the small sample size, the lack of biological samples to examine neurotrophic markers, and the inability to verify blast TBI diagnosis with MRI alone. They also note that normative modelling was limited by the absence of healthy controls, and that scanner or processing choices might affect results. The sample is described as highly selected and not broadly generalisable, consisting of physically trained male special operations veterans. The authors conclude that larger randomised controlled studies are needed to determine whether the effects are reproducible and whether they are driven by pharmacology, expectation, the therapeutic setting, or a combination of these factors.
Ibogaine is a naturally occurring psychoactive compound that has garnered interest as a rapid-acting therapeutic intervention for treating many psychiatric sequelae of TBI suffered by veterans, such as addiction, depression, and anxiety disorders.Animal studies have demonstrated the neuroplasticity-promoting effect of ibogaine through the transcriptional upregulation of glial cell-derived neurotrophic factor (GDNF),brain-derived neurotrophic factor (BDNF),and nerve growth factor.These effects may promote neural repair at the cellular level.The repair and replacement of damaged neural tissue may be associated with detectable increases in cortical thickness and volume.Regarding pharmacology, ibogaine (and its longer lasting metabolite, noribogaine) appears to interact with multiple neurotransmitter systems, including glutamatergic, nicotinic, sigma, mu and kappa opioid, serotonergic, and dopaminergic systems.While the central mechanism of ibogaine's effects is not yet confirmed, preclinical studies suggest that antagonism of glutamatergic N-methyl-d-aspartate (NMDA) receptors plays a critical role.Similarly, ibogaine is a noncompetitive inhibitor of the serotonin transporter, which may contribute meaningfully to its antidepressant and anxiolytic effects.Overall, ibogaine has a set of pharmacological and subjective effects that make it distinct from the more predominantly serotonergic classical psychedelics such as psilocybin.Despite its potential benefits, ibogaine is not without risk. The scientific literature reports at least 30 fatalities and toxic adverse events associated with ibogaine treatments,although deaths related to ibogaine tend to be associated with pre-existing med-ical conditions, overdose, and drug-drug interactions.Most notably, ibogaine's potential for causing QT prolongation and the development of Torsades de Pointes (TdP) poses a meaningful clinical challenge.Magnesium-Ibogaine Stanford Traumatic Injury to the CNS (MISTIC) is a therapeutic ibogaine protocol that incorporates the prophylactic co-administration of magnesium in an attempt to reduce potential cardiac-related risks without altering the ibogaine experience. It is worth noting that magnesium can also act as an NMDA antagonist,and there may therefore be additive antagonistic effects of ibogaine and magnesium on NMDA receptors.In a recently published first-of-its-kind observational pilot study,participants saw remarkable clinical improvements in self-reported disability, psychiatric symptom burden, cognitive and neuropsychological performance, and sleep. Although pre-post ibogaine studies in similar populations had been reported before,this 2024 articlewas the first reported study, to our knowledge, on co-administering ibogaine with magnesium. We hypothesized that these improvements would be accompanied by detectable changes in cortical thickness and volume using MRI. In the present study, we conducted a morphometric analysis of MRI data collected during the aforementioned clinical trialfocused on cortical thickness and parcellated brain volume. We also measured algorithmically predicted brain age by applying the brainageR algorithmto anatomical T1w MRIs from each visit. This algorithm has been used in several other published studies to characterize the accelerated brain aging often associated with TBI.Given the profound clinical efficacy reported previously by our group,our goal was to investigate whether morphometric changes in the brain post-ibogaine infusion accompany the previously reported clinical response in this sample. The three primary outcome measures being considered were changes from baseline to 1 month posttreatment in cortical thickness, subcortical volume, and predicted brain age. The human cerebral cortex is a highly folded sheet of gray matter (neurons) for which thickness is measured as the distance from the outer boundary (between gray matter and cerebrospinal fluid) to the inner boundary (between the gray matter and white matter),and this thickness typically ranges from 1 to 4.5 mm, with an overall average of approximately 2.5 mm, with large intraindividual variations.Cortical thickness is of great interest in normal development and as a marker of normal aging processes, as well as neurodegenerative and psychiatric disorders.A battery of methods has been developed for measuring cortical thickness from T1 MRI scans.Subcortical volume refers to the size (measured in cubic mm or cubic cm) of brain structures located ventrally and medially to the cerebral cortex. Subcortical volumes can be derived through the automated segmentation of MRI T1 scans using software such as Freesurferor ANTS,which identify boundaries between these structures and then estimate their volume.Predicted brain age is an age estimate produced by machine learning models trained on neuroimaging features, typically from structural MRI scans, reflecting the apparent biological age of the brain.There are a variety of brain age estimation algorithms available. The one used for the current study was brainageR, because of its prior use with TBI populations.iScience Article ll OPEN ACCESS
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Participant baseline characteristics are summarized in Table. Participants (25 male, mean age 44.5 years, SD = 7.0 years) had a combat exposure scale (CES) score of 29.9 (SD = 5.5), with an average of 65.2 TBIs in their lifetime. Of the 25 participants included, 23 had a mild TBI, 1 had a moderate TBI, and 1 had a moderately severe TBI.Six participants were unemployed at the time of the study, and 3/6 were unemployed due to disability. Participant characteristics across timepoints are summarized in Table.
We conducted a Wald Х 2 test of the whole-brain average cortical thickness LME model, which suggested a significant main effect of study visit (Х 2 = 7.23, p = 0.027). Estimated marginal means indicated a subtle increase in average cortical thickness from baseline (2.08 mm) to the initial post-treatment visit (2.13 mm) and 1-month follow-up (2.13 mm). Pairwise contrasts were trend-level after correction (0.05 < p holm < 0.1), consistent with a modest but directionally consistent global pattern of cortical thickening. Wald Х 2 tests of regional LME models revealed a significant (pFDR <0.05) main effect of study visit on cortical thickness in 13 of the 62 examined regions of interest (Figureand Table). Subsequent post-hoc pairwise t-tests demonstrated significant (p holm < 0.05) increases in cortical thickness initially following MISTIC therapy relative to the baseline visit in 11 regions (Figureand Table). We also observed significant increases in cortical thickness from baseline to 1-month following treatment in the rENT and the rpostC in addition to the aforementioned 11 regions. We found no significant changes between initial post and 1-month post visits, suggesting a likely sustained increase in estimated cortical thickness across the follow-up period. Additional estimated marginal means and post-hoc comparisons can be found in Tablesand. Overall, there were 11 cortical regions showing significant increases in thickness from baseline to initial post, 13 cortical regions showing significant increases in thickness from baseline to 1 month, and zero regions showing significant increases from initial post to 1 month.
We conducted Wald Х 2 tests of normative LME models, which revealed a significant main effect of study visit on the aggregate whole brain (X 2 = 6.724, p = 0.0347) and targeted normative percentile ranks (X 2 = 13.302, pFDR = 0.001293). Post-hoc testing revealed significant (p holm < 0.05) increases in targeted normative percentile rank between baseline and initial posttreatment MISTIC (estimated mean difference = +7.49 in relative percentile) and between baseline and 1-month post-MISTIC (Estimated Mean Difference = +8.70 in relative percentile). However, post-hoc testing for the whole brain analysis, we only identified trending increases in percentile rank between baseline and initial post-treatment MISTIC (Estimated Mean Difference = +4.921 in relative percentile) and between baseline and 1-month post-MISTIC (Estimated Mean Difference = +5.546 in relative percentile) (p holm = 0.077). Full ANOVA summary tables, estimated marginal means, pairwise contrasts, and panel figures can be found in Tables S9-S11 and Figure, respectively.
We conducted a Wald Х 2 test of the 28 subcortical LME models, which revealed a significant pFDR <0.05*) main effect of the
Past suicidal ideation 17 (68) Past suicide attempt 6 Past self harm 5 (20) AUD, alcohol use disorder; BATL, Boston Assessment of Traumatic Brain Injury-Lifetime; CES, combat exposure scale score; Chron. Age, chronological age in years; Nr. combat depl., number of deployed combats. a Nr. Of TBIs = number of traumatic brain injuries (lifetime). 3/25 participants had blast exposures too numerous to count and hence were unable to report an exact number of TBIs (NrTBIs). Hence, this value was imputed from the original cohort's (N = 30) mean and standard deviation (SD) as mean+5xSD. MDD, major depressive disorder; PTSD, post-traumatic stress disorder; SUD, substance use disorder. study visit on the log-jacobian determinant in 8 subcortical regions of interest (Figure). Post-hoc testing revealed significant (p holm < 0.05) volumetric expansion between the baseline and post-treatment MISTIC bilaterally in the cerebellar white matter, basal forebrain, and ventral diencephalon regions, as well as the right hippocampus. Sustained expansions (between baseline and 1-month post-treatment visits) were present bilaterally in the ventral diencephalon, the left cerebellar white matter, and the left basal forebrain, and we identified one volumetric contraction in the left caudate (Figure). We identified significant differences between the post-treatment and 1-month only in the right hippocampus, which reflects a transient observed volumetric expansion that returned to the baseline estimate at 1 month. Additional ANOVA results, estimated marginal means, and post-hoc comparisons can be found in Tables. Overall, 7 regions displayed a significant increase in volume from baseline to post-treatment, and 4 regions displayed a significant increase in volume from baseline to 1 month (and 1 region displayed a significant decrease over the same period), while no re-gions displayed a significant increase in volume from post-treatment to 1 month (and 1 region displayed a significant decrease over the same period).
Our exploratory analysis relating changes in cortical thickness, normative percentile estimates, and the log-jacobian determinant (summarized in supplemental information) to changes in the WHODAS-2.0 total score revealed no significant correlations.
pBA's produced by the brainageR algorithm ranged from a mean of 39.37 years (SD 10.24 years) at baseline to a mean of 38.54 years (SD 10.40 years) at the 1-month visit. The pBA mean values were slightly lower than chronological ages for this group, which ranged from a mean of 44.52 years (SD 7.01) at baseline to a mean of 44.86 years (SD = 7.32 years). Notably, chronological age, CES score, and number of TBIs were collected once atand). The LME model revealed a significant fixed effect of the variable of interest, study visit, on the dependent variable, pBA (X 2 = 6.967, p = 0.031*). Among the covariates, chronological age (X 2 = 12.25, p < 0.001***) and GM SNR (X 2 = 4.796, p = 0.029*) had significant effects on pBA (Table). Post-hoc pairwise comparisons revealed only a significant difference between the pBA estimated at the baseline visit and the 1-month post visit, giving an estimated marginal mean reduction in pBA of 1.3 years (Table; Figure).
Although potential associations were found between structural brain changes following ibogaine treatment and other study variables, none survived an FDR correction except for the association between pBA 1MnBL and HAM-A score at 1-month, normalized to baseline, but a subsequent linear regression did not find a predictive relationship. The relative lack of associations between the changes in brain morphometry and either psychiatric or neurocognitive assessments following MISTIC therapy may be due to inadequate sample size, as the present analysis included only 25 participants (22 when considering the 1-month visit). Previous research has demonstrated that relationships between brain morphometry and neurocognitive performance tend to have small effect sizes and require large samples with wide age ranges for adequately powered analyses.Moreover, the robust and largely uniform improvement in psychiatric symptoms following MISTIC therapy creates problems for linear statistical analyses (i.e., correlation and regression) that aim to explain the variance of dependent variables. Ergo, while these early patterns of increased cortical thickness, subcortical expansion, and decreases in pBA may be informative mechanistically, larger randomized controlled studies are necessary in order to formally study whether these changes are reproducible and, if so, whether they are related to the clinical effects of MISTIC therapy. For more on the relationship between behavioral and structural outcomes, and how we tested for them, please see the supplemental information.
Collectively, these results appear to provide the first assessment on a group level of MISTIC's effects on gross brain morphometry in humans over the course of a one-month period. Specifically, the present work provides the first preliminary characterization of ibogaine's effects on brain structure in a cohort of SOV with TBI. This is shown by decreases in pBA as well as longitudinal increases in cortical thickness and subcortical volume in regions that are relevant to the pathophysiology of TBI.The protocolized administration of ibogaine used in MISTIC 24 may induce detectable and lasting changes in brain structure in humans. These findings may reflect the growth of gray matter tissue through structural neural plasticityand support further investigation into the therapeutic potential of ibogaine in the context of TBI, neurodegenerative disease, and treatment-resistant neuropsychiatric conditions. Interpreting group-level changes in structural morphometry as an indication of therapeutic benefit comes with many challenges. Longitudinal T1 scans may be sensitive to nonstructural changes, such as changes in tissue water content,and even if increases in cortical thickness, subcortical volumetric expansion, and a decrease in pBA are indicative of structural neuroplastic change, it remains unclear whether these effects are indicative of enhancement/repair or, instead, could be maladaptive. Taken together, the normative analysis findings showing global and region-specific increases in cortical thickness trending toward the 50th percentile, along with reductions in pBA, suggest a pattern of structural change that could be related to the clinical and cognitive benefits described in our prior work, although the present data do not establish a mechanistic link. The results of this observational pilot study of special operations veterans (SOVs) who underwent MISTIC therapy demonstrated significant group-level increases in cortical thickness initially following MISTIC therapy. Moreover, these regional increases in thickness from baseline were also sustained at the 1-month visit, possibly suggesting durable effects. Areas of increased thickness after treatment were primarily observed in the right hemisphere, especially in the lateral prefrontal (rpORB, rpTRI), temporal (rMGH, rSTG, rENT), and parietal cortices (rIPL, rpostC). We also identified bilateral increases in cortical thickness in the medial occipital lobe (lLING, rLING) as well as the lateral orbitofrontal cortices (lLOF, rLOF). Notably, 10 out of 13 cortical regions showing significant increases in cortical thickness were lateralized to the right hemisphere, whereas a more symmetrical or global distribution of effects would be expected if changes were artifactual. Our findings are supported by previous functional imaging studies on the effects of hallucinogens, reporting increased regional cerebral blood flow and glucose uptake preferentially in the right hemisphere.While previous studies have found variable patterns of cortical thickness alterations in mild traumatic brain injury (mTBI) cohorts, frontal,temporal,and parietal lobethinning have been documented when comparing mTBI groups to healthy con-trols. Interestingly, within the specific context of military blast TBI, cortical thinning patterns have been observed bilaterally in the lateral orbitofrontal cortices, as well as in the right pars orbitalis and pars triangularis.Consequently, our finding of sustained cortical thickening in these regions is intriguing and possibly suggestive of a putative reversal-like phenomenon of the pathological cortical thinning patterns present in military blast TBI. Similarly, our log-jacobian determinant analysis revealed statistically significant group-level volumetric expansion following MISTIC therapy, although the timing of these effects was not as uniform as the cortical thickness analysis. Specifically, we identified significant volumetric expansion bilaterally in the cerebellum white matter as well as the basal forebrain, although these effects were only sustained at the 1-month post in the left hemisphere. The collection of heterogeneous structures that make up the basal forebrain area (most notably the basal nucleus of Meynert) has extensive projections to the cortex via both medial and lateral routes. Our analysis also identified a transient expansion in the right hippocampus immediately following MISTIC, as well as a significant volumetric contraction in the left caudate that was only present when comparing baseline and the 1-month post. The caudate is involved in a wide array of functions, including cognitive processes, emotional iScience Article regulation, motivation and goal-oriented behavior, and motor functions.Several studies have linked reduced caudate volumes to negative outcomes (e.g., PTSD); however, while the underlying mechanisms driving this volumetric contraction remain uncertain, and this finding was not consistent with our other results, alternative interpretations of such volumetric reductions are important to consider particularly in the context of improvement of symptoms on various behavioral outcomes and no significant adverse outcomes observed in this sample. One possibility refers to increased synaptic efficiency. Subcortical microstructural abnormalities in the caudate have been associated with PTSD and with impairments in several cognitive measures.Additionally, greater exposure to adverse childhood experiences (ACEs) may be associated with increased volume in the head of the left caudate.Previous studies theorized that the elimination of redundant synapses could improve computational efficiency via faster neuronal communication and promote the integration of brain function across diverse regions.Another potential example of this phenomenon is a recent study showing that mindfulness training may contribute to reductions in caudate gray matter volume and corresponding reductions in positive urgency, defined as the tendency to act impulsively in response to intense positive emotions.Moreover, volumetric analysis of alcohol-dependent patients has demonstrated that successfully treated patients who would later go on to relapse had elevated bilateral caudate volume at baseline, compared to nonrelapsing patients and healthy controls.Additionally, Schmidt and colleagues reported increases in caudate volume following 9 years of injectable opioid agonist treatment with diac-etylmorphine in 22 patients with opioid use disorder. Notably, the authors report that long-term opioid agonist treatment was associated with the enlargement of the right caudate nucleus, which was related to the duration of opioid use disorder.As such, the observed reductions in caudate volume may not imply maladaptive changes. Similar observations were made after the pharmacological treatment of patients with obsessive-compulsive disorder.Finally, we also identified statistically significant group-level expansion bilaterally in the ventral diencephalon (DC) from baseline to immediately following MISTIC therapy, which was also sustained at the 1-month visit. The ventral DC (as defined by the Mindboggle volumetric atlas) encompasses a collection of subthalamic structures,including the hypothalamus and mammillary bodies. Recent work has implicated this collection of structures in TBI,Alzheimer's disease,late-life depression,and CTE.To contextualize our findings of increased cortical thickness post-MISTIC, it is helpful to summarize similar findings from other interventions. For example, electroconvulsive therapy (ECT) is another rapid-acting intervention with high therapeutic efficacy for multiple conditions that is also associated with significant increases in cortical thickness within one week to several months post-ECT.With ECT, some trials have reported widespread increases in cortical thickness, including some regions that overlap with our findings, such as the inferior parietal gyrus, superior temporal gyrus, postcentral gyrus, right lateral occipital gyrus, and the right superior temporal gyrus. Similarly, although less rapid, pre-post MRI measurements of individuals undergoing antidepressant treatment with sertraline have demonstrated increased cortical thickness in some overlapping areas with our findings, such as medial orbitofrontal, lateral iScience Article occipital, inferior parietal, superior temporal, and pars triangularis,and other interventions such as exercise training,or cognitive training.A recently published case series demonstrated significant lesion reduction and structural changes following ibogaine treatments in two SOV with TBI who also presented with multiple sclerosis.Although there were some similarities in the spatial location and directionality of cortical thickness and subcortical volume changes, the small sample size, differences in scanning acquisition parameters, timing of scans, and neurological diagnoses preclude any formal comparisons of the findings to those of the present work. There are also numerous reports of widespread volumetric and cortical thickness enhancements associated with testosterone replacement therapyand parturition 100-102 with time scales as early as four weeks.It is, therefore, not unprecedented to find that a therapeutic intervention could result in significant increases in cortical thickness or volume. Finally, we note that although we observed significant increases in cortical thickness from baseline to initial post and from baseline to 1 month in many cases, the changes extant at the 1 month timepoint are perhaps more biologically plausible, given that variations at the initial post timepoint may be subject to nonstructural variation that T1 scans sometimes exhibit.
The significant reduction in pBA observed here is noteworthy and, importantly, distinct from the demonstrated tendency of certain personal characteristics and behaviors to be protective against accelerated brain aging. For example, female biological sex,Approximately two years following surgery, patients with mTLE (predominantly left-sided) demonstrated an average reduction in BAg of 5.17 years using the brain-ageR algorithm (same as the present study).The authors remark that their results support the proposal that mTLE is related to morphologic changes of accelerated aging and that surgical intervention may halt or possibly reverse this process. Studies using different brain-aging approaches from the present work have also demonstrated reductions in pBA. Le et al. reported that administering 200-600 mg of ibuprofen to 20 human participants in a placebo-controlled crossover design resulted in a mean reduction of 1.1 years in predicted brain age using a custom in-house algorithm.While that study did not identify a mechanism, the authors suggested that it may involve nonselective, reversible inhibition of COX-1, COX-2, and COX-independent pathways. Although no medical intervention was delivered, Luders et al. reported a mean reduction in BAg of 5.4 years between early (1-2 days) and late (4-6 weeks) postpartum stages in 14 healthy postpartum women 101 using the brain age framework outlined by Franke et al.While the authors did not identify a significant cor-relation between the changes in BAg and changes in serum concentrations of estradiol or progesterone, their later work frames the observed reductions in BAg within the context of early-tolate postpartum gray matter increases.Given that machine learning algorithms such as brainageR function in some ways as a black box, the inner workings of which are obscured from view, 111 interpreting these results can be challenging. As such, we emphasize caution when interpreting the reduction in pBA as indicating that the brains in question have become younger. More precisely, these results reflect the identification by a machine learning algorithm of anatomical MRI images that more closely resemble brains at an earlier point along the trajectory of healthy aging that it was trained on (James Cole, personal communication). In particular, the increases in cortical thickness reported here likely impacted the age estimates generated by the algorithm, given how consistently cortical thinning is associated with advancing pBA in normally aging individuals. 112 A neurobiological mechanism that may be involved in both outcomes, increased cortical thickness and reduced brain age, is the upregulation of neurotrophic factors such as BDNF and GDNF, which are associated with ibogaine administration in animal work.It is worth noting that, although TBI is frequently associated with accelerated pBA,participants in our study had pBAs that were already lower than their chronological ages, even at baseline. This may be attributable to selection effects; for example, to enter the special forces, these individuals all had to have exceptional physical fitness, which is protective against accelerated brain aging.It remains to be seen whether this effect would be found in a larger and more diverse cohort over a longer period of time. Although algorithmic brain age metrics such as predicted brain age are frequently associated with discrete neuroanatomical measures such as cortical thickness and/or hippocampal volume, such metrics do not appear to be reducible to specific neuroanatomical variables. In one dataset including male and female veterans, as well as male and female healthy controls, neuroanatomical variables such as cortical thickness were predictive of brain age metrics in some groups (patients with TBI) but not others (healthy controls).Additionally, brain age metrics may be more predictive of health trajectory than specific neuroanatomical variables taken by themselves. For example, one study found that brain age metrics were more predictive of the transition to Alzheimer's disease in an at-risk population than cortical thickness, and another study 118 found that among patients with Parkinson, brain age metrics predicted the development of MCI even when controlling for cortical thickness. Because algorithmic brain age metrics take a large number of neuroanatomical variables into account, as well as the relationships between them, they may reflect patterns more complex than what any discrete neuroanatomical variable can offer by itself. They have also been of particular interest in the veteran TBI population, where researchers have sought to use such measures to chart the enhanced risk of dementia found in such populations.Cerebellar effects Importantly, as described previously,all participants experienced transient cerebellar signs during MISTIC therapy, such as mild ataxia and intention tremor. Of note, these incidents iScience Article were transient and resolved within 24 h following MISTIC therapy completion. Early rat studies reported that high-dose ibogaine administration resulted in cerebellar Purkinje cell degeneration.These studies contextualize lingering concerns surrounding potential ibogaine-induced neurotoxicity. Although there are considerable limitations when making a cross-species comparison of ex vivo tissue histology findings in rats with the present volumetric neuroimaging analysis, we identified significant volumetric expansion (increase in the log-jacobian determinant) bilaterally in the cerebellar white matter following MISTIC therapy, and these changes were not accompanied by volumetric contraction in any cerebellar gray matter regions, which may support an interpretation that these effects were not detrimental, and possibly indicative of remyelination.Although we did not uncover any evidence of long-standing cerebellar toxicity in the present study, it is important to note that the resolution and specificity of our anatomical T1w MRI (0.9 mm isotropic) in comparison to that of postmortem histological analyses (microns) precludes any formal claims surrounding ibogaine's neurotoxicity profile in humans, although at least one postmortem neuropathological examination of a patient who used ibogaine on multiple occasions found no evidence of ibogaine-related neurotoxicity.We reported here on the structural neuroimaging results of an observational study in which thirty SOV, all diagnosed with TBI and multiple comorbidities, underwent MISTIC therapy and experienced substantial improvements in clinical and cognitive scores (as reported in prior work).We subsequently analyzed MRI data from 25 of those individuals. T1w MRIs were processed using a longitudinal pipeline developed by ANTs 125 in order to measure changes in cortical thickness and volumetric measures, and using the brainageRalgorithm in order to obtain pBAs. MISTIC therapy was associated with significant pre-to-post increases in cortical thickness, primarily at the 1-month visit, contrasted with baseline, and with significant pre-to-post reductions in pBA, also at the 1-month visit, contrasted with baseline. These changes in brain structure may, at least in part, be associated with the therapeutic action of ibogaine, although this remains to be established.
This study had a number of limitations. First, the lack of a control condition makes it difficult to evaluate whether the changes observed here were in some way due to a placebo effect. While it is unlikely that placebo effects could lead to structural brain changes, they could lead to the adoption of healthier lifestyles or reduced stress, which in turn could lead to structural brain changes.The ubiquity of such effects makes the interpretation of neuroimaging results something that should be engaged in with caution.Second, biological samples (i.e., blood, urine, and saliva) were not collected for this study, meaning we have little information about whether circulating levels of potentially relevant neurotrophic factors were changed by the treatment, and so we can only speculate about the potential role of those substances in producing the effects observed here. Of course, the limited sample size impairs our ability to detect small to moderate effects in this sample, a drawback that we hope can be addressed in future studies. Methodologically, we cannot exclude the possibility that our results might differ due to alternative image acquisition parameters, processing, or analytic approaches, although our comparison of the ANTs and Freesurfer pipelines was supportive of our current approach. Similarly, it is worthwhile to note that the formal diagnosis of blast-related TBI is based on clinical history and/or personal recollection, and verification is not currently possible with MRI alone and would require postmortem tissue analysis to identify astrocyte scarring.Additionally, for the normative modeling analysis, we were unable to apply a more sophisticated site-harmonization technique due to a lack of healthy control participants in our sample, and the dual differences of scanners and TBI cannot necessarily be untangled. However, while tentative and exploratory in nature, we think this is still potentially a valuable analysis for laying the groundwork for future studies to compare ibogaine effects to a normative sample. Finally, while our sample may be representative of highly trained male military SOVs with multiple blast injuries and superior physical fitness who are seeking ibogaine therapy, it is otherwise lacking in generalizability. Many questions remain about the effects of MISTIC and of ibogaine, more generally, on the human brain. Future studies will need to include more diverse patient samples to facilitate a broader understanding of the effects of ibogaine therapy. A randomized controlled trial of sufficient size and quality could determine whether the brain changes observed here result from pharmacology, expectation, the therapeutic environment, or, in the most likely case, all three. The predicted brain age of the participants was, on average, younger than their chronological age, despite this cohort all suffering from multiple TBIs, which are typically associated with predicted brain ages that are higher than the reported chronological age. We do not know what the reason for this was, although two candidate explanations are suggested here. First, participants in this study were all former SOF members with high levels of physical training, and who also mostly continued to engage in high levels of physical activity on a regular basis. Good cardiovascular health has been shown to be associated with lower predicted brain age.Second, this may be due to properties of the particular MRI that was used to collect images for this study, as we have observed similarly young predicted brain ages for participants in other studies we have conducted using this MRI. These factors should be considered in any future replication.
Requests for further information and resources should be directed to and will be fulfilled by the lead contact, John Coetzee (jpcoetzee@stanford.edu).
• Data: The deidentified human participant data reported in this study cannot be deposited in a public repository because they contain sensitive clinical and neuroimaging data from a vulnerable veteran population and are subject to Institutional Review Board-mandated controlled access. To request access, please contact the Stanford University Institutional Review Board and the study contact (John Coetzee, jpcoetzee@ iScience Article stanford.edu) with a research proposal and data security plan consistent with Stanford data-sharing requirements. The datasets used for normative modeling can be found here:. • Code: This article does not report original code. • Any additional information required to reanalyze the data reported in this article is available from the study contact upon request. = 256x256 voxel; TR = 6.39 ms, TE = 2.62 ms, slice thickness = 0.9 mm, flip angle = 12 • ). For each participant, MRI data were acquired at approximately the same time of day across all visits, with an average time difference of 1.5 h (±1.1 h) between visits. All participants were instructed to keep their heads still during the scan. Head motion was restricted using memory foam and inflatable padding. Additionally, participants' motion was monitored using in-scanner video cameras.
Of the 30 participants in the study, usable data from 25 participants' were included at the baseline and initial post-treatment visits, and 22 of these participants had available data for the 1-month post-treatment (this scan was not collected for all participants). Gray matter (GM) and white matter (WM) signal-to-noise ratio (SNR) estimates were calculated on the raw T1w MRI data using MRIQC.Because there are no explicit thresholds set for tissue-specific SNR by the authors, we leveraged their publicly available outputs of T1w MRI data from OSF,which yielded means and standard deviations of 10.52 (2.54) for GM SNR and 17.11 (5.45) for WM SNR. SNR from our data were consistent with these estimates (Table) over time.
For the present analysis, we derived cortical thickness measures for our participants with the ANTs longitudinal cortical thickness pipelineusing antsLongitudinalCorticalThickness.sh. The brain template, brain extraction probability mask, tissue segmentation priors, and brain extraction registration mask were derived from the OASIS template.Briefly, the longitudinal cortical thickness pipeline performs cortical thickness estimation for a longitudinal image series for a single subject by 1) creating an unbiased single-subject template (SST) from all time point images, 2) applying the ANTs cross-sectional cortical thickness pipeline antsCorti-calThickness.sh to the SST with group template and priors as input, 3) creating of the SST tissue prior probability maps, 4) rigidly transforming each individual time point to the SST, 5) applying the ANTs cross-sectional cortical thickness pipeline to each individual time-point image with the SST as a reference and finally 6) Joint label fusion using the Mindboggle OASIS-TRT-20 DKT 31 atlas labels 125 to determine cortical ROIs for statistical analysis. As such, a cortical thickness map for each study visit was output in the SST space for visual quality assurance, along with corresponding DKT 31 atlas ROIs and the estimated total intracranial volume (eTIV) of the SST for each participant. Regional mean cortical thickness estimates were derived using ImageIntensityStatistics, and 62 (31L | 31R) cortical ROIs were evaluated statistically. The ANTs pipeline has been shown to perform exceptionally well for registration 125 as well as cortical thickness measurement in terms of minimal failure rate, higher reproducibility, and improved predictive performance in thousands of images, even compared to the state-of-the-art.The ANTs cortical thickness pipeline has also been implemented in morphometric studies of TBI,Alzheimer's disease, 137,138 depression,and temporal lobe epilepsy.As both methods are frequently used in morphometric studies, we also employed the Freesurfer (7.4.0) longitudinal processing pipeline in parallel, and trained raters performed visual inspection and subsequent manual longitudinal editing steps to correct skull-stripping, tissue (WM, Pial) boundary, and atlas labeling errors. DKT 31 atlas ROI cortical thickness estimates were extracted for each participant by study visit. As pipeline evaluation metrics, we performed test-retest reliability and unidimensional reliability analyses for cortical thickness estimates across regions between the two pipelines (see supplemental information for details). Those analyses suggested the superiority of the ANTs pipeline compared to FreeSurfer with respect to our specific dataset and informed the decision to conduct the formal analysis using ANTs.
As part of the ANTs longitudinal cortical thickness pipeline, 142 log-jacobian determinant maps are also output for each time point in the SST space. Each value in the log-jacobian map quantifies the relative expansion or contraction of the time point image relative to the (OASIS) study template wherein negative values indicate the time point image < study template and positive values indicate the time point image > study template. We evaluated volumetric statistics in 28 subcortical and cerebellar ROIs from the Mindboggle volumetric atlas using ImageIntensityStatistics similar to cortical thickness measurements yielding regional mean log-jacobian determinant estimates.Statistical analysis -repeated measures Before evaluating regional effects, we first assessed longitudinal change in whole-brain average cortical thickness using a linear mixed-effects model with the same covariates described below (Visit, age, CES, nrTBIs, eTIV, and a random intercept). This provided an overall measure of global cortical change across visits. To evaluate longitudinal changes in cortical thickness and volume across the 62|28 cortical |subcortical ROIs, we employed linear mixed effects models in R (4.2.0) using the lmer function from the lme4 package. Consistent with the modeling used in our previous work,for each ROI, a linear mixed effect model was constructed to determine the main effect of the study visit while covarying for chronological age, combat exposure scale (CES), the number of TBIs (nrTBIs), and the eTIV with a random intercept, and using restricted maximum likelihood (REML).