Manual scoring of periodic limb movements in children: is it still necessary?

OBJECTIVE: Although manual scoring has been classically considered the gold standard to identify periodic leg movements (PLM), it is a very time consuming and expensive process, also subject to variability in interpretation. In the last decades, different authors have observed reasonably good agreement between automated PSG scoring algorithms and manual scoring in adults, according to established criteria. We aim to compare the automatic software analysis of our polysomnogram with the manual staging in children with sleep-disordered breathing. METHODS: We performed a semiautomatic method, in which an experienced technician watched the video recording and removed from the automatic analysis those movements that did not correspond to true candidate leg movement (LM). RESULTS: A total of 131 PSGs were studied; applying the established criteria, 65 children were diagnosed of obstructive sleep apnea, and 66 presented snoring but with no sleep apnea. The mean age was 6.7 years (±1.7) and twenty-five children (19.08 %) had a PLMI >5/h. Statistical differences were found not only for PLMI (manual: 2.20 (0.7, 4.1) vs automatic (6.4 (3.85,9.5); p < 0.001), but for almost of all indexes assessed between the automatic and the manual scoring analysis. The level of concordance was only moderate for PLM index (0.63 [0.51-0.72]); showing that, unlike the articles published in the adult population, automatic analysis is not accurate in children and, manually or semi-automatically analysis as ours need to be done. CONCLUSION: It seems that PLM detection algorithm might work accurately but, the real need would be a true LM detection algorithm.

A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep.

In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit. Highlights: Benzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.

Effect of positive airway pressure treatment on excessive fragmentary myoclonus in 100 sleep-related breathing disorder patients.

STUDY OBJECTIVES: Excessive fragmentary myoclonus (EFM) is a frequent finding in patients undergoing video-polysomnography (VPSG). We aimed to evaluate the potential effect of sleep-related breathing disorder's treatment with positive airway pressure (PAP) therapy on EFM. METHODS: One hundred consecutive patients with EFM and sleep-related breathing disorder subsequently treated with PAP at the sleep lab of the Medical University of Innsbruck, Department of Neurology, Austria, were included. Each patient underwent two nights of VPSG: the first night without and the second night with PAP therapy. Fragmentary myoclonus was automatically scored with validated software, and fragmentary myoclonus index (FMI) and minutes of non-rapid eye movement (NREM) sleep with EFM (minNREM+EFM) were calculated. RESULTS: Under PAP therapy there was a significant decrease in the minNREM+EFM - 60.5 (9.5-161.8) at baseline vs. 37.5 (6.3-168.8) minutes under PAP, p = 0.025. No significant differences were observed for FMI between the two nights. Sleep variables, sleep diagnoses, comorbidities, and medication did not influence FMI or the minNREM+EFM. CONCLUSIONS: The initiation of PAP treatment led to a significant reduction of minNREM+EFM, but not of FMI. The results suggest that PAP therapy might influence the distribution of FM potentials.

Periodic limb movement disorder in children: A systematic review.

This systematic review evaluates the scientific literature on pediatric periodic limb movement disorder (PLMD), adhering to PRISMA guidelines and utilizing PICOS criteria. The search across PubMed, EMBASE, and Scopus yielded 331 articles, with 17 meeting inclusion criteria. Diagnostic criteria evolved, with polysomnography and PLMS index ≥5 required since 2003. Also, PLMD diagnosis mandates clinical consequences like insomnia, hypersomnia, and fatigue, excluding comorbidities causing sleep disruption. Prevalence in children is low (0.3%), emphasizing the need for meticulous investigation. Comorbidities, particularly the bidirectional relationship with ADHD, were explored. Challenges in diagnosis and understanding arise from overlapping conditions such as sleep disordered breathing, psychotropic medication, and criteria non-adherence. Despite generally good study quality, weaknesses include sample size justification and biases. The periodic leg movement index shows high sensitivity but low specificity, underscoring strict diagnostic criteria adherence. Diverse metrics for symptoms necessitate standardized approaches. Family history of RLS in children with PLMD suggests unexplored aspects. Treatment, mainly iron supplementation, lacks standardized assessment metrics. The review emphasizes diagnostic and treatment challenges, recommending unbiased studies with precise techniques. Comprehensive research, quantifying PLMS and objectively assessing sleep parameters, is crucial for advancing understanding in pediatric PLMD. PROSPERO REGISTRATION NUMBER: CRD42021251406.

Changes in time structure of periodic leg movements during sleep in restless legs syndrome: Effects of sex and age.

BACKGROUND: The objective of this study was to check the hypothesis that in women with restless legs syndrome (RLS) different changes occur in periodic leg movements during sleep (PLMS) during the post-menopausal period (using >50 years as a proxy) than in men of the same age. METHODS: We recruited 36 untreated patients aged 18-50 years (19 men, median age 40 years, and 17 women, median age 37 years) while the remaining 67 were >50 years old (24 men, median age 66.6 years, and 43 women, median age 60.0 years). Leg movement activity during sleep was analyzed by means of an approach utilizing indexes especially suitable to assess leg movement periodicity. RESULTS: No significant difference was seen between men in the two age groups; conversely, in women, a clear and significant increase in Periodicity Index was observed in the older group, along with a decrease in isolated leg movements. In women, a clear age-related enhancement of PLMS was found in the intermovement interval graphs, especially in the 16-22 s range, which was more evident than that observed in men. The results remained unchanged also when they were replicated by selecting only subjects aged 18-45 years vs. those aged >55 years. CONCLUSIONS: Our findings indicate that assessing PLMS in women after menopause is clinically relevant because they are probably connected with the hormonal fluctuations of this period of life. Translationally, identifying and addressing PLMS in post-menopausal women is crucial for optimizing their sleep health and addressing potential health risks associated with sleep disturbances.

Coexistence of periodic limb movements during sleep with restless legs syndrome and its association with hypertension in Japanese patients.

BACKGROUND: Caucasian patients with restless legs syndrome (RLS) frequently exhibit periodic limb movements during sleep (PLMS), which may increase the risk of hypertension. We evaluated the positivity rate of PLMS and factors associated with positivity in Japanese patients with RLS, and tested whether the complications of PLMS are associated with the presence of hypertension. METHODS: We retrospectively investigated polysomnographic data and the presence or absence of hypertension in patients with RLS. Patients with systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or those taking antihypertensive medication were categorized as the group with hypertension. RESULTS: Among 468 patients, 200 (42.7%) had periodic limb movement index (PLMI) values ≥ 15/h and 108 (23.1%) met the criteria of positivity for hypertension. Multiple logistic regression analysis revealed that only higher age was significantly associated with PLMI values ≥ 15/h. Multiple linear regression analyses of factors associated with an increased PLMI also showed that increased PLMI was significantly correlated with higher age and male sex, but not with the international restless legs scale scores. Multiple logistic regression analysis also revealed that higher age and body mass index, not PLMI values ≥ 15/h, were significantly associated with the presence of hypertension. CONCLUSION: The PLMS-positivity rate may be lower in Japanese patients with RLS than in Caucasian patients, and it increases with age and male sex, but not with the severity of the disorder. Furthermore, PLMS complications were not associated with the risk of hypertension in Japanese patients with RLS.

Association of Periodic Limb Movements and Obstructive Sleep Apnea With Risk of Cardiovascular Disease and Mortality.

BACKGROUND: Obstructive sleep apnea is a well-established risk factor for cardiovascular disease (CVD). Recent studies have also linked periodic limb movements during sleep to CVD. We aimed to determine whether periodic limb movements during sleep and obstructive sleep apnea are independent or synergistic factors for CVD events or death. METHODS AND RESULTS: We examined data from 1049 US veterans with an apnea-hypopnea index (AHI) <30 events/hour. The primary outcome was incident CVD or death. Cox proportional hazards regression assessed the relationships between the AHI, periodic limb movement index (PLMI), and the AHI×PLMI interaction with the primary outcome. We then examined whether AHI and PLMI were associated with primary outcome after adjustment for age, sex, race and ethnicity, obesity, baseline risk of mortality, and Charlson Comorbidity Index. During a median follow-up of 5.1 years, 237 of 1049 participants developed incident CVD or died. Unadjusted analyses showed an increased risk of the primary outcome with every 10-event/hour increase in PLMI (hazard ratio [HR], 1.08 [95% CI, 1.05-1.13]) and AHI (HR, 1.17 [95% CI, 1.01- 1.37]). Assessment associations of AHI and PLMI and their interaction with the primary outcome revealed no significant interaction between PLMI and AHI. In fully adjusted analyses, PLMI, but not AHI, was associated with an increased risk of primary outcome: HR of 1.05 (95% CI, 1.00-1.09) per every 10 events/hour. Results were similar after adjusting with Framingham risk score. CONCLUSIONS: Our study revealed periodic limb movements during sleep as a risk factor for incident CVD or death among those who had AHI <30 events/hour, without synergistic association between periodic limb movements during sleep and obstructive sleep apnea.

Generalised linear model of periodic limb movements.

During sleep, the lower extremities exhibit periodic repetitive movements which are referred to as Period Limb Movement (PLM). Polysomnography (PSG) is the gold standard for diagnosing periodic limb movement disorder. The frequency of PLM episodes per hour of sleep (PLMI) determines the severity of the condition. PLM are generated by a dynamic process, however PLMI measures only the average PLM rate and does not capture the dynamic properties of PLM. Here, we characterise PLM dynamics using a generalised dynamic model as a function of sleep stage, timing of past PLM events and adjacent sleep disordered-breathing events. We analysed PSG recordings of 237 men and 222 women enrolled in the Multi-ethnic Study of Atherosclerosis (MESA) dataset to model dynamic PLM features. We statistically analysed whether these dynamics are associated with sex, age, and BMI. Modelling suggests instantaneous PLM rates are greater in men than women and higher in N1 and N2 non-rapid eye movement sleep than N3 and rapid eye movement sleep. The generalised model constitutes statistically robust approach towards the characterisation of periodic limb movement.Clinical Relevance- The generalised model may enable differentiated diagnostics of periodic limb movement disorder.

[Abnormal nocturnal behavior mimicking REM sleep behavior disorder episodes in a patient with periodic limb movement disorder].

Periodic limb movement disorder (PLMD) is a condition in which patients experience frequent periodic limb movements of sleep (PLMS). Synchronized arousal responses cause sleep fragmentation, resulting in insomnia, daytime sleepiness, and fatigue. A 59-year-old man was identified as having intense sleep-talking and body movements, suggesting rapid eye movement (REM) sleep behavior disorder (RBD). Attended video-polysomnography (PSG) revealed that sleep-talking and body movements occurred only during non-REM sleep and were associated with PLMS-induced arousals (periodic leg movement arousal index, 53.2/h). Pramipexole administration improved events during sleep and daytime sleepiness, and the PSG findings and clinical course led to a diagnosis of PLMD. This case demonstrates that PLMD mimics the symptoms of RBD and that a detailed analysis of monitored video PSG is crucial to confirm the diagnosis of RBD and to identify or exclude other causes of sleep talking and behavior.

[Restless sleep disorder a new entity to considered in children]. / Trastorno de sueño inquieto: una nueva entidad clínica a considerar en niños.

Restless sleep disorder (RSD) is a condition recently described by a group of sleep experts who developed diagnostic and polysomnographic criteria after conducting a comprehensive review of the available literature where poor sleep or restless sleep is a symptom alone or that accompanies other disorders. This group defined RSD as a condition characterized by parental complaints of frequent jerking movements during sleep, position changes, and sleep disruption that cause significant impairment during the day. Diagnostic criteria include the presence of symptoms for at least 3 months, 3 times a week, and at least 5 movements per hour on polysomnography. Changes in behavior during the day, such as drowsiness, irritability, and hyperactivity that are not explained by a medical, pharmacological, or behavioral condition, should be considered. Its estimated prevalence is 7.7% of children referred for sleep problems. Children often have ferritin levels below 50 µg/l, a point in common with restless legs syndrome. Treatment consists of iron supplements, which have shown benefits in these children. To establish the diagnosis, secondary symptoms of medical origin or other sleep disorders such as restless legs syndrome or periodic limb movement disorder must be ruled out. The objective of this report is to review the current recommendations on this entity, describe the clinical, pathophysiological, and polysomnographic keys, in order to highlight the need to publicize this condition and expand studies in age groups other than those already defined and to generate treatment guidelines.

Periodic leg movements during sleep and cognitive functioning in the older general population.

OBJECTIVE: The current evidence of a relationship between periodic leg movements during sleep (PLMS) and cognitive functioning is limited and inconsistent. This cross-sectional study assessed associations between PLMS and cognitive functioning among community-dwelling older adults. METHODS: We included community-dwelling older adults who underwent a polysomnography and a cognitive assessment. The PLMS index (PLMI) and PLMS arousal index (PLMAI) were categorized into tertiles: PLMI <5/h (reference), 5-29.9/h, ≥30/h; and PLMAI <1/h (reference), 1-4.9/h, ≥5/h. The cognitive assessment consisted of ten scores covering the main cognitive domains: global cognition, processing speed, executive function, language, episodic verbal memory, and visuospatial function. Associations between PLMI, PLMAI, and cognitive scores were assessed using regression unadjusted and adjusted models. RESULTS: A total of 579 individuals without dementia were included (mean age: 71.5 ± 4.4 years; men 45.4%). The number of participants in the high-PLMI categories, 5-29.9/h and ≥30/h, was 185 (32.0%) and 171 (29.5%), respectively. Participants in the high-PLMI categories showed no significant difference compared to the reference group regarding their cognitive performance according to the unadjusted and adjusted models. Similarly, we found no association between PLMAI severity and cognitive functioning. CONCLUSIONS: This study shows no cross-sectional association between PLMS severity and cognitive functioning among community-dwelling older adults. However, given the paucity of data in this field, further studies are needed to clarify the relationship between PLMS and cognitive functioning.

[Periodic limb movements in sleep and cerebral small vessel disease progression: a prospective cohort study]. / Periodicheskie dvizheniya konechnostei vo sne i progressirovanie tserebral'noi mikroangiopatii: prospektivnoe kogortnoe issledovanie.

OBJECTIVE: To determine the predictive role of periodic limb movements in sleep (PLMS) in cerebral small vessel disease (cSVD) progression rate. MATERIAL AND METHODS: Fifty patients with cSVD, aged 60-75 y.o., were enrolled. The study protocol included MRI assessment of white matter hyperintensities (WMH), nocturnal actigraphy and cognitive assessment. Depending on the PLMS, the main (PLM index ≥15) and the control (PLM index <15) groups were formed. The second visit was carried out in one year follow-up period, the examination consisted of brain MRI and cognitive assessment under the same protocol. ANCOVA was performed to determine if PLMS influence the degree of MRI- and neuropsychological changes. RESULTS: A significant effect of PLMS on the increase in the volume of WMH was revealed, both in the form of an increase in the index by more than 15 movements per hour (p=0.03), and quantitatively in the form of a connection with the index value (p=0.048). The influence of PLMS on the progression of cognitive dysfunction has not been found, however, it has been shown that the presence of PLMS is associated with lesions in the deep white matter (r=0.42, p<0.0001), and the results of neuropsychological tests are associated with lesions in the periventricular and juxtacortical WMH (p < 0.05 for each test). CONCLUSION: PLMS predict WMH progression in cSVD.

A 9-year-old female with iron deficiency has severe periodic limb movements while taking mirtazapine for insomnia.

Mirtazapine is a Food and Drug Administration-approved atypical antidepressant used off-label for insomnia. Mirtazapine has been associated with movement disorders in adults. A 9-year-old female was seen in the sleep clinic for symptoms of insomnia, nocturnal awakenings, restless sleep, and growing pains. Mirtazapine was started prior to presentation for severe insomnia. A sleep study showed frequent repetitive leg movements prior to sleep onset as well as significant periodic limb movement disorder with a periodic limb movement index of 25.1/hour. The child was found to have a ferritin level of 23 ng/mL and an iron saturation of 10%. There were concerns that the presence of iron deficiency along with the use of mirtazapine may have contributed to the elevated periodic limb movement index. After starting iron therapy to treat the child's iron deficiency, mirtazapine was weaned off, with further clinical improvements in sleep quality reported. A follow-up sleep study showed a resolution of her periodic limb movement disorder with a periodic limb movement index of 1.4/hour. This is the first pediatric case to describe a sleep-related movement disorder associated with the use of mirtazapine and polysomnographic data to support resolution after discontinuation of mirtazapine along with iron therapy. CITATION: Hawkins M. A 9-year-old female with iron deficiency has severe periodic limb movements while taking mirtazapine for insomnia. J Clin Sleep Med. 2023;19(7):1369-1373.

Restless Legs Syndrome and Periodic Limb Movements of Sleep: From Neurophysiology to Clinical Practice.

SUMMARY: This article summarizes restless legs syndrome (RLS), periodic limb movements of sleep, and periodic limb movement disorder. RLS is a common sleep disorder with a prevalence of 5% to 15% in the general population. RLS can present in childhood, and incidence increases with age. RLS can be idiopathic or secondary to iron deficiency, chronic renal failure, peripheral neuropathy, and medications such as antidepressants (with higher rates for mirtazapine and venlafaxine, while bupropion may reduce symptoms at least in the short term), dopamine antagonists (neuroleptic antipsychotic agents and antinausea medications), and possibly antihistamines. Management includes pharmacologic agents (dopaminergic agents, alpha-2 delta calcium channel ligands, opioids, benzodiazepines) and nonpharmacologic therapies (iron supplementation, behavioral management). Periodic limb movements of sleep are an electrophysiologic finding commonly accompanying RLS. On the other hand, most individuals with periodic limb movements of sleep do not have RLS. The clinical significance of the movements has been argued. Periodic limb movement disorder is a distinct sleep disorder that arises in individuals without RLS and is a diagnosis of exclusion.

Time to rest a hypothesis? Accumulating evidence that periodic leg movements during sleep are not increased in children with attention-deficit hyperactivity disorder (ADHD): results of a case-control study and a meta-analysis.

STUDY OBJECTIVES: To address the hypothesis that periodic leg movements during sleep (PLMS) are more frequent in children with attention-deficit hyperactivity disorder (ADHD) when compared with typically developing (TD) children. To that end, we analyzed PLMS in a recent case-control study and conducted a systematic review and meta-analysis of PLMS frequency in children with ADHD and TD children. METHODS: In our case-control study, we compared the PLMS frequency of 24 children with ADHD (mean age 11 years, 17 males) to that of 22 age-matched typically developing (TD) children (mean age 10 years, 12 males). A subsequent meta-analysis included 33 studies that described PLMS frequency in groups of children with ADHD and/or groups of TD children. RESULTS: The case-control study did not show any differences in the frequency of PLMS between children with ADHD and TD children, a result that was consistent across a range of different definitions of PLMS, which in turn had a significant and systematic effect on PLMS frequency. The meta-analysis compared the average PLMS indices and the proportion of children with elevated PLMS indices between children with ADHD and TD children and across a number of analyses did not find any meta-analytic results that supported the hypothesis that PLMS are more frequent in children with ADHD. CONCLUSIONS: Our results suggest that PLMS are not more frequent in children with ADHD compared with TD children. A finding of frequent PLMS in a child with ADHD should therefore be considered a separate disorder and prompt specific diagnostic and therapeutic strategies.

Periodic limb movements during sleep and risk of hypertension: A systematic review.

BACKGROUND: Several studies suggest an association between periodic limb movements during sleep (PLMS) and hypertension; however, a systematic evaluation of this relationship is lacking. METHODS: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio, or standardized incidence ratio, comparing the risk of hypertension in persons with PLMS (defined by the level of periodic limb movements per hour of sleep depended on individual studies) versus those without PLMS. After assessing heterogeneity and bias, the pooled risk ratio and 95% confidence intervals (CIs) were determined using a random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Out of 572 potentially relevant articles, six eligible studies were included in the data analysis. Studies (6 cross-sectional) included 8949 participants. The statistical heterogeneity of this study was insignificant, with an I2 of 0%. A funnel plot and Egger's regression asymmetry test showed no publication bias with P-value ≥0.05. The pooled risk ratio of hypertension in patients with PLMS was 1.26 (95% CI, 1.12-1.41). CONCLUSIONS: Our analysis demonstrates an increased hypertension risk among patients with PLMS. Prospective or interventional studies are needed to confirm this association.

Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis.

STUDY OBJECTIVES: Periodic limb movements during sleep (PLMS) are a frequent finding in restless legs syndrome, but their impact on sleep is still debated, as well the indication for treatment. We systematically reviewed the available literature to describe which drug categories are effective in suppressing PLMS, assessing their efficacy through a meta-analysis, when this was possible. METHODS: The review protocol was preregistered on PROSPERO (CRD42021175848), and the systematic search was conducted on and EMBASE (last searched on March 2020). We included original human studies, which assessed PLMS modification on drug treatment with a full-night polysomnography, through surface electrodes on each tibialis anterior muscle. When at least 4 studies were available on the same drug or drug category, we performed a random-effect model meta-analysis. RESULTS: Dopamine agonists like pramipexole and ropinirole resulted the most effective, followed by l-dopa and other dopamine agonists. Alpha2delta ligands are moderately effective as well opioids, despite available data on these drugs are much more limited than those on dopaminergic agents. Valproate and carbamazepine did not show a significant effect on PLMS. Clonazepam showed contradictory results. Perampanel and dypiridamole showed promising but still insufficient data. The same applies to iron supplementation. CONCLUSIONS: Dopaminergic agents are the most powerful suppressors of PLMS. However, most therapeutic trials in restless legs syndrome do not report objective polysomnographic findings, there is a lack of uniformity in presenting results on PLMS. Longitudinal polysomnographic interventional studies, using well-defined and unanimous scoring criteria and endpoints on PLMS are needed. CITATION: Riccardi S, Ferri R, Garbazza C, Miano S, Manconi M. Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis. J Clin Sleep Med. 2023;19(4):811-822.

Periodic limb movements in sleep are linked to decreased hippocampus and amygdala volumes in the population-based BiDirect Study.

STUDY OBJECTIVES: Even though numerous studies indicate that sleep disorders are associated with altered brain morphology, MRI studies focusing on periodic limb movements in sleep (PLMS) are scarce. Our aim was to investigate the association of PLMS with global and regional gray matter volumes as well as white matter hyperintensity (WMH) volume. METHODS: One hundred and eighty-nine subjects (57.0 ± 7.8 years, women: 50.5%) of the population-based BiDirect Study underwent a single-night polysomnography (PSG). Standard criteria of the American Academy of Sleep Medicine were applied to evaluate sleep characteristics and calculate the PLMS index (PLMSI). T1w and FLAIR images were acquired with cerebral MRI at 3 Tesla. Voxel-based morphometry was performed to determine the total gray matter volume as well as the volume of cortical segments and subcortical gray matter areas using SPM12 and CAT12. The WMH volume was quantified with the Brain Intensity AbNormality Classification Algorithm. The independent relationship between MRI markers and PLMSI was analyzed using multivariable linear regression with adjustment for age, sex, body mass index, intracranial volume, PSG scorer, PSG device, sleep apnea, and the use of antidepressants. RESULTS: PLMSI was not significantly related to global gray matter volume and WMH volume. However, significant inverse associations of the PLMSI with the volume of the hippocampus (left and right hemisphere) and left amygdala were observed. CONCLUSIONS: A significant relationship between a higher PLMSI and lower volumes of the hippocampus and amygdala was found among the participants of the BiDirect Study. Since these associations are based on exploratory analyses, further replications are required before drawing firm conclusions.