Hippocampal Shape Is Associated with Memory Deficits in Temporal Lobe Epilepsy.

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.

Repetitive Transcranial Magnetic Stimulation-Induced Neuroplasticity and the Treatment of Psychiatric Disorders: State of the Evidence and Future Opportunities.

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.

TMS-induced plasticity improving cognitive control in OCD II: Task-based neural predictors of treatment response.

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.

Transcranial Magnetic Stimulation-Induced Plasticity Improving Cognitive Control in Obsessive-Compulsive Disorder, Part I: Clinical and Neuroimaging Outcomes From a Randomized Trial.

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 3 different rTMS protocols, all combined with exposure and response prevention. METHODS: In this 3-arm proof-of-concept randomized trial, 61 treatment-refractory adult patients with OCD received 16 sessions of rTMS immediately before exposure and response prevention over 8 weeks, with task-based functional magnetic resonance imaging scans and clinical assessments before and after treatment. Patients received high-frequency rTMS to the left dorsolateral prefrontal cortex (n = 19 [13 women/6 men]), high-frequency rTMS to the left pre-supplementary motor area (preSMA) (n = 23 [13 women/10 men]), or control rTMS to the vertex (n = 19 [13 women/6 men]). Changes in task-based functional magnetic resonance imaging activation before/after 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 (Δ = -10.836, p < .001, 95% CI -12.504 to -9.168), with no differences between groups. Response rate in the entire sample was 57.4%. The dorsolateral prefrontal cortex rTMS group showed decreased planning-related activation after treatment that was associated with greater symptom improvement. No group-level activation changes were observed for the preSMA and vertex rTMS groups. Participants in the preSMA group with greater symptom improvement showed decreased error-related activation, and symptom improvement in the vertex group was associated with increased inhibition-related activation. CONCLUSIONS: rTMS to preSMA and dorsolateral prefrontal cortex combined with exposure and response prevention led to activation decreases in targeted task networks in individuals showing greater symptom improvement, although we observed no differences in symptom reduction between groups.

Sleep predicts the response to rTMS and CBT in patients with OCD: an open label effectiveness study.

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.

Progressive Cortical Thinning in Patients With Focal Epilepsy.

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.