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OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has the potential to increase the clinical effect of exposure with response prevention (ERP) psychotherapy for obsessive-compulsive disorder (OCD). We investigated the use of task-based functional MRI (tb-fMRI) for predicting clinical outcomes to different rTMS protocols combined with ERP in OCD. METHOD: 61 adults with OCD underwent rTMS and ERP and were randomized to different high frequency rTMS conditions: left dorsolateral prefrontal cortex (DLPFC; n=19), left pre-supplementary motor area (preSMA; n=23), and control stimulation at the vertex at low intensity (n=19). The Tower of London task and Stop-Signal Task were used to assess pretreatment activation during planning and inhibitory control, respectively. We adopted a Bayesian region-based approach to test whether clinical improvement can be predicted by tb-fMRI-derived measures of task-related brain activation or functional connectivity between task-relevant regions and the bilateral amygdala. RESULTS: For the vertex group, but not the DLPFC/preSMA rTMS conditions, higher activation in several task-relevant regions during planning and response inhibition, and lower error-related activation, corresponded with better short-term clinical improvement. Lower precuneus activation with increased planning taskload correlated with symptom reduction in the DLPFC group. In the preSMA group, higher error-related activation and lower inhibition-related insular-amygdalar connectivity was associated with symptom reduction. CONCLUSIONS: Pretreatment tb-fMRI-derived measures of activation and connectivity during planning and inhibition-related processes are associated with clinical response for specific rTMS conditions in OCD. Future placebo-controlled trials with larger sample sizes should combine clinical information and neural correlates to improve prediction of clinical outcome.

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BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following three different rTMS stimulation protocols, all combined with exposure and response prevention (ERP). METHODS: In this three-arm proof-of-concept randomized trial, 61 treatment-refractory adult OCD patients received 16 sessions of rTMS immediately prior to ERP over 8 weeks, with task-based functional MRI (tb-fMRI) scans and clinical assessments pre- and post-treatment. Patients received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC)(n=19(6M/13F)); HF rTMS to the left pre-supplementary motor area (preSMA)(n=23(10M/13F)); or control rTMS to the vertex(n=19(6M/13F)). Changes in tb-fMRI activation pre-post treatment were compared using both a Bayesian region-of-interest and a general linear model whole-brain approach. RESULTS: Mean OCD symptom severity decreased significantly in all treatment groups (delta=-10.836, p<0.001, 95% CI[-12.504,-9.168]), with no differences between groups. Response rate in the entire sample was 57.4%. The DLPFC rTMS group showed decreased planning-related activation post-treatment that was associated with greater symptom improvement. No group-level activation changes were observed for the preSMA or vertex rTMS groups. Participants with greater symptom improvement in the preSMA group showed decreased error-related activation, and symptom improvement in the vertex group was associated with increased inhibition-related activation. CONCLUSIONS: PreSMA and DLPFC rTMS combined with ERP led to activation decreases in targeted task networks in individuals showing greater symptom improvement, although we observed no differences in symptom reduction between groups.

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Neuroplasticity, or activity-dependent neuronal change, is a crucial mechanism underlying the mechanisms of effect of many therapies for neuropsychiatric disorders, one of which is repetitive transcranial magnetic stimulation (rTMS). Understanding the neuroplastic effects of rTMS at different biological scales and on different timescales and how the effects at different scales interact with each other can help us understand the effects of rTMS in clinical populations and offers the potential to improve treatment outcomes. Several decades of research in the fields of neuroimaging and blood biomarkers is increasingly showing its clinical relevance, allowing measurement of the synaptic, functional, and structural changes involved in neuroplasticity in humans. In this narrative review, we describe the evidence for rTMS-induced neuroplasticity at multiple levels of the nervous system, with a focus on the treatment of psychiatric disorders. We also describe the relationship between neuroplasticity and clinical effects, discuss methods to optimize neuroplasticity, and identify future research opportunities in this area.

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Background: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment option for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have, however, been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following three different rTMS stimulation protocols, all combined with exposure and response prevention (ERP). Methods: In this three-arm proof-of-concept randomized controlled clinical trial, 61 treatment-refractory adult OCD patients received 16 sessions of rTMS immediately prior to ERP over 8 weeks, with task-based functional MRI (tb-fMRI) scans and clinical assessments pre- and post-treatment. Patients received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC) (n=19 (6M/13F)); HF rTMS to the left pre-supplementary motor area (preSMA) (n=23 (10M/13F)); or control rTMS to the vertex (n=19 (6M/13F)). Changes in tb-fMRI activation pre-post treatment were compared using both a Bayesian region-of-interest and a general linear model whole-brain approach. Results: Mean OCD symptom severity decreased significantly in all treatment groups (delta=- 10.836, p<0.001, 95% CI [-12.504, -9.168]), with no differences between groups. Response rate in the entire sample was 57.4%. Groups receiving DLPFC or preSMA rTMS showed, respectively, a decrease in planning and error processing task-related activation after treatment that was associated with symptom improvement, while individuals in the vertex rTMS group with greater symptom improvement showed an increase in inhibition-related activation. Conclusions: PreSMA and DLPFC rTMS combined with ERP led to significant symptom improvement related to activation decreases in targeted task networks, although we observed no differences in symptom reduction between groups. This trial was registered at clinicaltrials.gov ( NCT03667807 ).

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Background: Although many OCD patients benefit from repetitive transcranial magnetic stimulation (rTMS) as treatment, there is still a large group failing to achieve satisfactory response. Sleep problems have been considered transdiagnostic risk factors for psychiatric disorders, and prior work has shown comorbid sleep problems in OCD to be associated with non-response to rTMS in OCD. We therefore set out to investigate the utility of sleep problems in predicting response to rTMS in treatment resistant OCD. Method: A sample of 61 patients (treated with 1-Hz SMA or sequential 1-Hz SMA+DLPFC rTMS, combined with cognitive behavioral therapy) were included. Sleep disturbances were measured using the PSQI, HSDQ and actigraphy. Treatment response was defined as a decrease of at least 35% in symptom severity as measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Results: 32 of 61 patients (52.5%) responded to rTMS, and trajectories of response were similar for both rTMS protocols. Three PSQI items (Subjective Sleep Quality; Sleep Latency and Daytime Dysfunction) and the HSDQ-insomnia scale were found to predict TMS response. A discriminant model yielded a significant model, with an area under the curve of 0.813. Conclusion: Future replication of these predictors could aid in a more personalized treatment for OCD. (AU)

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Background: Although many OCD patients benefit from repetitive transcranial magnetic stimulation (rTMS) as treatment, there is still a large group failing to achieve satisfactory response. Sleep problems have been considered transdiagnostic risk factors for psychiatric disorders, and prior work has shown comorbid sleep problems in OCD to be associated with non-response to rTMS in OCD. We therefore set out to investigate the utility of sleep problems in predicting response to rTMS in treatment resistant OCD. Method: A sample of 61 patients (treated with 1-Hz SMA or sequential 1-Hz SMA+DLPFC rTMS, combined with cognitive behavioral therapy) were included. Sleep disturbances were measured using the PSQI, HSDQ and actigraphy. Treatment response was defined as a decrease of at least 35% in symptom severity as measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Results: 32 of 61 patients (52.5%) responded to rTMS, and trajectories of response were similar for both rTMS protocols. Three PSQI items (Subjective Sleep Quality; Sleep Latency and Daytime Dysfunction) and the HSDQ-insomnia scale were found to predict TMS response. A discriminant model yielded a significant model, with an area under the curve of 0.813. Conclusion: Future replication of these predictors could aid in a more personalized treatment for OCD.

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OBJECTIVE: Cognitive problems, especially disturbances in episodic memory, and hippocampal sclerosis are common in temporal lobe epilepsy (TLE), but little is known about the relationship of hippocampal morphology with memory. We aimed to relate hippocampal surface-shape patterns to verbal and visual learning. METHODS: We analyzed hippocampal surface shapes on high-resolution magnetic resonance images and the Adult Memory and Information Processing Battery in 145 unilateral refractory TLE patients undergoing epilepsy surgery, a validation set of 55 unilateral refractory TLE patients, and 39 age- and sex-matched healthy volunteers. RESULTS: Both left TLE (LTLE) and right TLE (RTLE) patients had lower verbal (LTLE 44 ± 11; RTLE 45 ± 10) and visual learning (LTLE 34 ± 8, RTLE 30 ± 8) scores than healthy controls (verbal 58 ± 8, visual 39 ± 6; p < 0.001). Verbal learning was more impaired the greater the atrophy of the left superolateral hippocampal head. In contrast, visual memory was worse with greater bilateral inferomedial hippocampal atrophy. Postsurgical verbal memory decline was more common in LTLE than in RTLE (reliable change index in LTLE 27% vs RTLE 7%, p = 0.006), whereas there were no differences in postsurgical visual memory decline between those groups. Preoperative atrophy of the left hippocampal tail predicted postsurgical verbal memory decline. INTERPRETATION: Memory deficits in TLE are associated with specific morphological alterations of the hippocampus, which could help stratify TLE patients into those at high versus low risk of presurgical or postsurgical memory deficits. This knowledge could improve planning and prognosis of selective epilepsy surgery and neuropsychological counseling in TLE. ANN NEUROL 2020 ANN NEUROL 2020;88:170-182.

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OBJECTIVE: To examine the shared familial contribution to hippocampal and extrahippocampal morphological abnormalities in patients with sporadic temporal lobe epilepsy (TLE) and their unaffected siblings. METHODS: We collected clinical, electrophysiological, and T1-weighted magnetic resonance imaging (MRI) data of 18 sporadic patients with TLE without lesions other than hippocampal sclerosis (12 right, 6 left), their 18 unaffected full siblings, and 18 matched healthy volunteers. We compared between-group differences in cortical thickness and volumes of five subcortical areas (hippocampus, amygdala, thalamus, putamen, and pallidum). We determined the subregional extent of hippocampal abnormalities using surface shape analysis. All our imaging results were corrected for multiple comparisons using random field theory. RESULTS: We detected smaller hippocampal volumes in patients (right TLE: median right hippocampus 1.92 mL, interquartile range [IQR] 1.39-2.62, P < .001; left TLE: left hippocampus 2.05 mL, IQR 1.99-2.33, P = .01) and their unaffected siblings (right hippocampus 2.65 mL, IQR 2.32-2.80, P < .001; left hippocampus 2.39 mL, IQR 2.18-2.53, P < .001) compared to healthy controls (right hippocampus 2.94 mL, IQR 2.77-3.24; left hippocampus 2.71 mL, IQR 2.37-2.89). Surface shape analysis showed that patients with TLE had bilateral subregional atrophy in both hippocampi (right > left). Similar but less-pronounced subregional atrophy was detected in the right hippocampus of unaffected siblings. Patients with TLE had reduced cortical thickness in bilateral premotor/prefrontal cortices and the right precentral gyrus. Siblings did not show abnormalities in cortical or subcortical areas other than the hippocampus. SIGNIFICANCE: Our results demonstrate a shared vulnerability of the hippocampus in both patients with TLE and their unaffected siblings, pointing to a contribution of familial factors to hippocampal atrophy. This neuroimaging trait could represent an endophenotype of TLE, which might precede the onset of epilepsy in some individuals.

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IMPORTANCE: It is controversial whether epilepsy is a static or progressive disease. Evidence of progressive gray matter loss in epilepsy would support early diagnosis, rapid treatment, and early referral for surgical interventions. OBJECTIVE: To demonstrate progressive cortical thinning in patients with focal epilepsy distinct from cortical thinning associated with normal aging. DESIGN, SETTING, AND PARTICIPANTS: A case-control neuroimaging study was conducted from August 3, 2004, to January 26, 2016, among 190 patients with focal epilepsy at a tertiary epilepsy referral center (epilepsy data) and 3 independent comparison cohorts matched for age and sex (healthy volunteer data; n = 141). EXPOSURES: Two or more high-resolution T1-weighted magnetic resonance imaging scans at least 6 months apart (mean [SD] interval, 2.5 [1.6] years). MAIN OUTCOMES AND MEASURES: Global and vertexwise rate of progressive cortical thinning. RESULTS: A total of 190 people with focal epilepsy (99 women and 91 men; mean [SD] age, 36 [11] years; 396 magnetic resonance imaging scans) were compared with 141 healthy volunteers (76 women and 65 men; mean [SD] age, 35 [17] years; 282 magnetic resonance imaging scans). Widespread highly significant progressive cortical thinning exceeding normal aging effects, mainly involving the bilateral temporal lobes, medial parietal and occipital cortices, pericentral gyri, and opercula, was seen in 146 individuals with epilepsy (76.8%; 95% CI, 58%-95%). The mean (SD) annualized rate of global cortical thinning in patients with epilepsy was twice the rate of age-associated thinning observed in healthy volunteers (0.024 [0.061] vs 0.011 [0.029] mm/y; P = .01). Progression was most pronounced in adults older than 55 years and during the first 5 years after the onset of seizures. Areas of accelerated cortical thinning were detected in patients with early onset of epilepsy and in patients with hippocampal sclerosis. Accelerated thinning was not associated with seizure frequency, history of generalized seizures, or antiepileptic drug load and did not differ between patients with or without ongoing seizures. Progressive atrophy in temporal (n = 101) and frontal (n = 28) lobe epilepsy was most pronounced ipsilaterally to the epileptic focus but also affected a widespread area extending beyond the focus and commonly affected the contralateral hemisphere. For patients with temporal lobe epilepsy, accelerated cortical thinning was observed within areas structurally connected with the ipsilateral hippocampus. CONCLUSIONS AND RELEVANCE: Widespread progressive cortical thinning exceeding that seen with normal aging may occur in patients with focal epilepsy. These findings appear to highlight the need to develop epilepsy disease-modifying treatments to disrupt or slow ongoing atrophy. Longitudinal cortical thickness measurements may have the potential to serve as biomarkers for such studies.