Auditory neurophysiological development in early childhood: A growth curve modeling approach

ObjectiveDuring early childhood, the development of communication skills, such as language and speech perception, relies in part on auditory system maturation. Because auditory behavioral tests engage cognition, mapping auditory maturation in the absence of cognitive influence remains a challenge. Furthermore, longitudinal investigations that capture auditory maturation within and between individuals in this age group are scarce. The goal of this study is to longitudinally measure auditory system maturation in early childhood using an objective approach.MethodsWe collected frequency-following responses (FFR) to speech in 175 children, ages 3–8 years, annually for up to five years. The FFR is an objective measure of sound encoding that predominantly reflects auditory midbrain activity. Eliciting FFRs to speech provides rich details of various aspects of sound processing, namely, neural timing, spectral coding, and response stability. We used growth curve modeling to answer three questions: 1) does sound encoding change across childhood? 2) are there individual differences in sound encoding? and 3) are there individual differences in the development of sound encoding?ResultsSubcortical auditory maturation develops linearly from 3-8 years. With age, FFRs became faster, more robust, and more consistent. Individual differences were evident in each aspect of sound processing, while individual differences in rates of change were observed for spectral coding alone.ConclusionsBy using an objective measure and a longitudinal approach, these results suggest subcortical auditory development continues throughout childhood, and that different facets of auditory processing follow distinct developmental trajectories.SignificanceThe present findings improve our understanding of auditory system development in typically-developing children, opening the door for future investigations of disordered sound processing in clinical populations.     

Age-related changes in late synaptic inputs to corticospinal neurons and their functional significance: A paired-pulse TMS study

BackgroundRecent work suggests that the function of intracortical interneurons activated by transcranial magnetic stimulation (TMS) is modified in older adults, with the circuits generating short-interval intracortical facilitation (SICF) at longer intervals appearing to be particularly affected.ObjectiveTo use SICF to quantify age-related changes in the excitability and recruitment of late synaptic inputs to corticospinal neurons, and investigate if changes within these circuits contribute to altered motor performance in older adults.MethodsSICF was recorded with 3 different conditioning intensities in 23 young (23.0 ± 4.2 years) and 21 older (67.1 ± 1.1 years) adults. These measures were performed with conventional (posterior-anterior, PA) and reverse (anterior-posterior, AP) current directions using interstimulus intervals targeting late synaptic inputs to corticospinal neurons (3.5–5.3 ms).ResultsPeak SICF recorded with a PA current (SICF_PA) was reduced in older adults (P < 0.0001), and occurred at a longer latency (P < 0.05). Furthermore, there was reduced recruitment of SICF_PA in older adults (P < 0.0001), but this did not interact with the age-related shift in SICF_PA (P = 0.2). In addition, reduced performance on the Purdue pegboard was predicted by increased SICF_PA (P < 0.04) occurring at longer latencies (P < 0.04) in old but not young adults. For SICF recorded with an AP current (SICF_AP), facilitation was again reduced at longer latencies in older adults (P < 0.0001), but recruitment was not different between groups (P = 0.7) and was unrelated to motor function.ConclusionThese results suggest that there are age-related changes in late synaptic inputs to corticospinal neurons and that these changes influence fine motor performance.     

Bradykinesia in Alzheimer’s disease and its neurophysiological substrates

ObjectiveAlzheimer’s disease is primarily characterized by cognitive decline; recent studies, however, emphasize the occurrence of motor impairment in this condition. Here, we investigate whether motor impairment, objectively evaluated with kinematic techniques, correlates with neurophysiological measures of the primary motor cortex in Alzheimer’s disease.MethodsTwenty patients and 20 healthy subjects were enrolled. Repetitive finger tapping was assessed by means of a motion analysis system. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and short-latency afferent inhibition. Plasticity-like mechanisms were indexed according to changes in motor-evoked potential amplitude induced by the intermittent theta-burst stimulation.ResultsPatients displayed slowness and altered rhythm during finger tapping. Movement slowness correlated with reduced short-latency afferent inhibition in patients, thus suggesting that degeneration of the cholinergic system may also be involved in motor impairment in Alzheimer’s disease. Moreover, altered movement rhythm in patients correlated with worse scores in the Frontal Assessment Battery.ConclusionThis study provides new information on the pathophysiology of altered voluntary movements in Alzheimer’s disease.SignificanceThe study results suggest that a cortical cholinergic deficit may underlie movement slowness in Alzheimer’s disease.     

No enhanced (p-) α-synuclein deposition in gastrointestinal tissue of Parkinson's disease patients

BackgroundNeuronal alpha-synuclein (α-Syn) aggregation in the brain is believed to be a central component of the pathogenesis of Parkinson's disease (PD). α-Syn aggregates in the gastrointestinal tract have been suggested as a potential biomarker of PD that may even signal an early event of the Parkinsonian molecular pathology. However, studies further investigating this hypothesis have produced mixed results.ObjectiveTo determine whether the prevalence of α-Syn- and serine 129-phosphorylated α-Syn (Ser129p-α-Syn) depositions detected in intestine from PD patients differed from that of non-Parkinsonian controls.MethodsIn this retrospective study, we examined post-mortem small and large intestine samples of 25 PD patients and 20 age- and sex-matched controls without PD. Specimens were taken from archived paraffin-embedded tissue blocks. Immunohistochemical techniques were applied to detect α-Syn and Ser129p-α-Syn aggregates in situ. Immunoreactivity was quantified by a new approach that employed the detailed assessment of α-Syn- and Ser129p-α-Syn-positive morphological structures of the enteric nervous system (i.e., nerve fibers, myenteric and submucous plexus as well as ganglion cells).Resultsα-Syn immunoreactivity was a common finding in intestinal tissues from PD patients and controls. Importantly, α-Syn and Ser129p-α-Syn immunoreactivity were significantly reduced in PD patients compared to controls in each of the morphological structures examined.ConclusionsImmunohistochemical detection of intestinal α-Syn and Ser129p-α-Syn seems to be a frequent and potentially normal finding. Neither α-Syn nor Ser129p-α-Syn immunoreactivity may, therefore, be regarded as a molecular intestinal biomarker of PD pathology. Reduced intestinal α-Syn and Ser129p-α-Syn immunoreactivity in PD patients rather reflect PD-related neuronal degeneration.     

Progressive microstructural alterations in subcortical nuclei in Parkinson's disease: A diffusion magnetic resonance imaging study

ObjectivesTo explore the microstructural alterations in subcortical nuclei in Parkinson's disease (PD) at different stages with diffusion kurtosis imaging (DKI) and tensor imaging and to test the performance of diffusion metrics in identifying PD.Methods108 PD patients (64 patients in early-stage PD group (EPD) and 44 patients in moderate-late-stage PD group (MLPD)) and 64 healthy controls (HC) were included. Tensor and kurtosis metrics in the subcortical nuclei were compared. Partial correlation was used to correlate the diffusion metrics and Unified Parkinson's Disease Rating Scale part-III (UPDRS-III) score. Logistic regression and receiver operating characteristic analysis were applied to test the diagnostic performance of the diffusion metrics.ResultsCompared with HC, both EPD and MLPD patients showed higher fractional anisotropy and axial diffusivity, lower mean kurtosis (MK) and axial kurtosis in substantia nigra, lower MK and radial kurtosis (RK) in globus pallidus (GP) and thalamus (all p < 0.05). Compared with EPD, MLPD patients showed lower MK and RK in GP and thalamus (all p < 0.05). MK and RK in GP and thalamus were negatively correlated with UPDRS-III score (all p < 0.01). The logistic regression model combining kurtosis and tensor metrics showed the best performance in diagnosing PD, EPD, and MLPD (areas under curve were 0.817, 0.769, and 0.914, respectively).ConclusionsPD has progressive microstructural alterations in the subcortical nuclei. DKI is sensitive to detect microstructural alterations in GP and thalamus during PD progression. Combining kurtosis and tensor metrics can achieve a good performance in diagnosing PD.     

Parkinson's disease advanced therapies - A systematic review: More unanswered questions than guidance

In advanced Parkinson's disease (PD), therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion (CSAI), levodopa-carbidopa intestinal gel (LCIG) infusion, and deep brain stimulation (DBS). We reappraised the evidence guiding the decision of appropriate device-aided therapies in advanced PD, and systematically reviewed the literature (including ongoing clinical trials) comparing CSAI, LCIG, DBS in terms of efficacy and cost-effectiveness, with particular consideration to possible conflicts of interests. Of 14,980 documents screened, sixteen were included (4 and 13 studies examining efficacy and cost-effectiveness, respectively). LCIG and DBS showed higher efficacy compared to best medical therapy (BMT). DBS was more expensive than BMT and LCIG. Lifetime costs of CSAI were lower of those of DBS, and DBS lifetime costs were lower than those of LCIG. The majority of studies (11 out of 16) showed direct or indirect sponsorship from pharmaceutical or device companies. Only one ongoing clinical trial comparing LCIG with DBS was found. Device-aided therapies address unmet needs in advanced PD. LCIG and DBS are superior to BMT in head-to-head studies; however, initial and lifetime costs should be considered when choosing those therapies. Guidelines to assist clinicians and patients to choose device-aided therapies, free from conflict of interests, are required.     

Association of lipid levels with motor and cognitive function and decline in advanced Parkinson's disease in the Mark-PD study

ObjectivesIn prospective cohort studies different blood lipid fractions have been identified as risk factors of Parkinson's disease (PD). However, data relating lipoproteins to disease phenotypes and progression in advanced PD patients are sparse. Therefore, we assessed the most common lipoproteins in a case-control design and evaluated their associations with motor and cognitive function and decline in PD patients.MethodsTriglycerides, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein a (Lp(a)) were analyzed in 294 PD patients of the MARK-PD study cohort and 588 controls matched for age, sex and cardiovascular risk factors. In PD patients, motor (MDS-UPDRS III, Hoehn-Yahr stage) and cognitive function (MoCA) were examined. In a sub-cohort (n = 98 patients), baseline lipid levels were correlated with motor and cognitive disease progression during a follow-up period of 523 ± 199 days.ResultsAt baseline, HDL-C levels were lower in PD patients compared to matched controls after adjustment. We observed a very weak association of Lp(a) levels with UDPRS III scores. In cross-sectional analyses, no other lipid fraction revealed a significant and consistent association with motor or cognitive function. During follow-up, no lipid fraction level was associated with motor or cognitive progression.ConclusionIn advanced PD, there is no strong and consistent association of lipid levels with motor or cognitive function and decline.     

Subthalamic nucleus deep brain stimulation improves sleep in Parkinson's disease patients: a retrospective study and a meta-analysis

BackgroundMost Parkinson's patients suffered from sleep problems. There is increasing evidence that Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) has a positive effect on several sleep parameters, improving overall sleep quality in patients with PD. However, the results are controversial.MethodsWe performed a retrospective study and meta-analysis to assess the Parkinson's disease sleep scale (PDSS) in Parkinson's patients.ResultsWe reviewed our data of patients who underwent STN-DBS, and then extracted five other trials to perform a meta-analysis. The pooled results showed an advantage on post-operative PDSS in both our medical center and pooled results (MD = 20.41, 95% CI = [13.03, 27.79], I² = 61%, P < 0.001). There was a significant difference in Unified Parkinson's Disease Rating Scale (UPDRS)-Ⅲ score between pre and post-operation (MD = −12.59, 95% CI = [−14.70, −10.49], I² = 90%, P < 0.001). What's more, Parkinsonian medication was significantly lower in the post-operative groups after DBS (MD = −314.71, 95% CI = [−468.13, −161.28], I² = 53%, P < 0.001).ConclusionIn the retrospective study and meta-analysis of 6 trials, we found that DBS can significantly increase sleep quality. Furthermore, motor function improved and Parkinsonian medication was significantly decreased postoperatively. The sample size was enough and no further investigations would change the conclusion.     

Automated assessment of the substantia nigra on susceptibility map-weighted imaging using deep convolutional neural networks for diagnosis of Idiopathic Parkinson's disease

ObjectivesDespite its use in determining nigrostriatal degeneration, the lack of a consistent interpretation of nigrosome 1 susceptibility map-weighted imaging (SMwI) limits its generalized applicability. To implement and evaluate a diagnostic algorithm based on convolutional neural networks for interpreting nigrosome 1 SMwI for determining nigrostriatal degeneration in idiopathic Parkinson's disease (IPD).MethodsIn this retrospective study, we enrolled 267 IPD patients and 160 control subjects (125 patients with drug-induced parkinsonism and 35 healthy subjects) at our institute, and 24 IPD patients and 27 control subjects at three other institutes on approval of the local institutional review boards. Dopamine transporter imaging served as the reference standard for the presence or absence of abnormalities of nigrosome 1 on SMwI. Diagnostic performance was compared between visual assessment by an experienced neuroradiologist and the developed deep learning-based diagnostic algorithm in both internal and external datasets using a bootstrapping method with 10000 re-samples by the “pROC” package of R (version 1.16.2).ResultsThe area under the receiver operating characteristics curve (AUC) (95% confidence interval [CI]) per participant by the bootstrap method was not significantly different between visual assessment and the deep learning-based algorithm (internal validation, .9622 [0.8912–1.0000] versus 0.9534 [0.8779-0.9956], P = .1511; external validation, 0.9367 [0.8843-0.9802] versus 0.9208 [0.8634-0.9693], P = .6267), indicative of a comparable performance to visual assessment.ConclusionsOur deep learning-based algorithm for assessing abnormalities of nigrosome 1 on SMwI was found to have a comparable performance to that of an experienced neuroradiologist.     

Genetic analysis of ATP10B for Parkinson's disease in Japan

Compound heterozygosity of ATP10B is thought to be a risk factor for young-onset Parkinson's disease (PD). We genetically screened 245 patients with young-onset sporadic PD and 33 patients with autosomal recessive PD for ATP10B. All 13 identified gene variants were heterozygous with little evidence of the pathogenicity.     

Progressive loss of raphe nuclei serotonin transporter in early Parkinson's disease: A longitudinal 123I-FP-CIT SPECT study

BackgroundSerotonergic raphe nuclei dysfunction has been documented in Parkinson's disease, both in pathological and neuroimaging studies, and has been associated with scores of tremor and non-motor symptoms. However, no in vivo longitudinal investigations have been conducted to assess the rate of decline of raphe serotonin transporter availability in the early stages of the disease.ObjectiveTo measure the rate of decline of raphe serotonin transporter availability over a two-year interval in patients with recently diagnosed disease and its association with non-motor symptoms over time.MethodsBaseline and two-year follow-up ¹²³ioflupane-fluoropropyl-carbomethoxy-3-beta-4-iodo-phenyltropane (¹²³I-FP-CIT) SPECT scans of 173 early Parkinson's disease patients enrolled in the Parkinson's Progressive Markers Initiative were analysed and non-motor symptoms scores recorded.ResultsA 16.6 ± 20.9% (mean ± SD) reduction in raphe serotonin transporter availability was found from baseline to two-year follow-up in the entire cohort. No differences in progression were found between tremor dominant and postural instability/gait difficulty phenotypes. At follow-up 34.1% of patients showed a moderate-to-severe reduction of raphe serotonin transporter availability with respect to the controls’ mean. We did not find any significant correlation between raphe serotonin transporter availability and scores of depression, excessive daytime sleepiness and REM sleep behaviour disorder.Conclusion¹²³I-FP-CIT SPECT was able to measure longitudinal reductions in raphe serotonin transporter availability in the early phases of Parkinson's disease. About four years after diagnosis, raphe serotonin transporter availability was significantly reduced in more than one third of the population, but does not appear to be correlated to non-motor symptoms at this stage.     

α and θ oscillations in the subthalamic nucleus are potential biomarkers for Parkinson's disease with depressive symptoms

IntroductionAbnormal α oscillations in the bed nucleus of stria terminalis and subgenual cingulate of patients with depression correlate with symptom severity. Some Parkinson's disease (PD) patients also have abnormal θ-α oscillations in the subthalamic nucleus (STN). However, the relationship between abnormal θ-α oscillations and depressive symptoms in PD patients has not been determined. This study explored the correlation between α and θ oscillations of the STN and depressive symptoms in PD patients.MethodsWe conducted a retrospective case-control study on 36 PD patients with (dPD group) or without depressive symptoms (nPD group), analyzing the difference in the average power spectral density (PSD) of α and θ oscillations of the local field potential (LFP) recorded in the STN during deep brain stimulation (DBS), and their correlation with the Hamilton depression rating scale (HAMD) of PD patients during the same period.ResultsThe dPD group had a higher PSD of α oscillations and a lower PSD of θ oscillations in the left ventral STN. The PSD of α oscillations of the left ventral STN were positively correlated with the severity of depressive symptoms, whereas the PSD of θ oscillations of this location was negatively correlated with severity of depressive symptoms. The PSD of α and θ oscillations did not correlate with motor symptoms, sleep quality, or quality of life score.ConclusionAbnormal α and θ oscillations of the left ventral STN could be used as biomarkers of PD with depressive symptoms, which might guide STN-DBS treatment.     

TMS brain mapping of the pharyngeal cortical representation in healthy subjects

BackgroundBrain mapping is fundamental to understanding brain organization and function. However, a major drawback to the traditional Brodmann parcellation technique is the reliance on the use of postmortem specimens. It has therefore historically been difficult to make any comparison regarding functional data from different regions or hemispheres within the same individual. Moreover, this method has been significant limited by subjective boundaries and classification criteria and therefore suffer from reproducibility issues. The development of transcranial magnetic stimulation (TMS) offers an alternative approach to brain mapping, specifically the motor cortical regions by eliciting quantifiable functional reactions.ObjectiveTo precisely describe the motor cortical topographic representation of pharyngeal constrictor musculature using TMS and to further map the brain for use as a tool to study brain plasticity.Methods51 healthy subjects (20 male/31 female, 19–26 years old) were tested using single-pulse TMS combined with intraluminal catheter-guided high-resolution manometry and a standardized grid cap. We investigated various parameters of the motor-evoked potential (MEP) that include the motor map area, amplitude, latency, center of gravity (CoG) and asymmetry index.ResultsCortically evoked response latencies were similar for the left and right hemispheres at 6.79 ± 0.22 and 7.24 ± 0.27 ms, respectively. The average scalp positions (relative to the vertex) of the pharyngeal motor cortical representation were 10.40 ± 0.19 (SE) cm medio-lateral and 3.20 ± 0.20 (SE) cm antero-posterior in the left hemisphere and 9.65 ± 0.24 (SE) cm medio-lateral and 3.18 ± 0.23 (SE) cm antero-posterior in the right hemisphere. The mean motor map area of the pharynx in the left and right hemispheres were 9.22 ± 0.85(SE) cm²and 10.12 ± 1.24(SE) cm², respectively. The amplitudes of the MEPs were 35.94 ± 1.81(SE)uV in the left hemisphere and 34.49 ± 1.95(SE)uV in the right hemisphere. By comparison, subtle but consistent differences in the degree of the bilateral hemispheric representation were also apparent both between and within individuals.ConclusionThe swallowing musculature has a bilateral motor cortical representation across individuals, but is largely asymmetric within single subjects. These results suggest that TMS mapping using a guided intra-pharyngeal EMG catheter combined with a standardized gridded cap might be a useful tool to localize brain function/dysfunction by linking brain activation to the corresponding physical reaction.     

Decline in drawing ability and cerebral perfusion in Parkinson's disease patients after subthalamic nucleus deep brain stimulation surgery

BackgroundSubthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for alleviating motor symptoms in advanced Parkinson's disease (PD) patients; however, a postoperative decline in cognitive and speech function has become problematic although its mechanism remains unclear. The aim of the present study was to elucidate the properties of language and drawing ability and cerebral perfusion in PD patients after bilateral STN DBS surgery.MethodsWestern aphasia battery, including drawing as a subcategory, and perfusion (N-isopropyl-p-[¹²³I] iodoamphetamine) SPECT scan was conducted in 21 consecutive PD patients, before, and three to six months after, bilateral STN DBS surgery while on stimulation. Perfusion images were compared with those of 17 age- and gender-matched healthy volunteers. In the parametric image analysis, the statistical peak threshold was set at P < 0.001 uncorrected with a cluster threshold set at P < 0.05 uncorrected.ResultsAlthough motor symptoms were improved and general cognition was preserved in the patient group, 11 patients (52.4%) showed a decline in the drawing subcategory after surgery, which showed a reduction in Frontal Assessment Battery score in this group of patients. Statistical parametric analysis of the brain perfusion images showed a decrease of cerebral blood flow in the prefrontal and cingulate cortex after surgery. Patients whose drawing ability declined showed decreased perfusion in the middle cingulate cortex comparing before and after surgery.ConclusionPresent results show that some PD patients show a decline in drawing ability after bilateral STN DBS which may attributable by dysfunction in the cingulate network.     

Altered sensorimotor integration in multiple sclerosis: A combined neurophysiological and functional MRI study

ObjectiveTo explore whether abnormal thalamic resting-state functional connectivity (rsFC) contributes to altered sensorimotor integration and hand dexterity impairment in multiple sclerosis (MS).MethodsTo evaluate sensorimotor integration, we recorded kinematic features of index finger abductions during somatosensory temporal discrimination threshold (STDT) testing in 36 patients with relapsing-remitting MS and 39 healthy controls (HC). Participants underwent a multimodal 3T structural and functional MRI protocol.ResultsPatients had lower index finger abduction velocity during STDT testing compared to HC. Thalamic rsFC with the precentral and postcentral gyri, supplementary motor area (SMA), insula, and basal ganglia was higher in patients than HC. Intrathalamic rsFC and thalamic rsFC with caudate and insula bilaterally was lower in patients than HC. Finger movement velocity positively correlated with intrathalamic rsFC and negatively correlated with thalamic rsFC with the precentral and postcentral gyri, SMA, and putamen.ConclusionsAbnormal thalamic rsFC is a possible substrate for altered sensorimotor integration in MS, with high intrathalamic rsFC facilitating finger movements and increased thalamic rsFC with the basal ganglia and sensorimotor cortex contributing to motor performance deterioration.SignificanceThe combined study of thalamic functional connectivity and upper limb sensorimotor integration may be useful in identifying patients who can benefit from early rehabilitation to prevent upper limb motor impairment.     

Prediction of motor Unified Parkinson's Disease Rating Scale scores in patients with Parkinson’s disease using surface electromyography

ObjectiveParkinson's disease (PD) is a chronic neurodegenerative disorder with increasing prevalence in the elderly. Especially patients with advanced PD often require complex medication regimens due to fluctuations, that is abrupt transitions from ON to OFF or vice versa. Current gold standard to quantify PD-patients’ motor symptoms is the assessment of the Unified Parkinson's Disease Rating Scale (UPDRS), which, however, is cumbersome and may depend upon investigators. This work aimed at developing a mobile, objective and unobtrusive measurement of motor symptoms in PD.MethodsData from 45 PD-patients was recorded using surface electromyography (sEMG) electrodes attached to a wristband. The motor paradigm consisted of a tapping task performed with and without dopaminergic medication. Our aim was to predict UPDRS scores from the sEMG characteristics with distinct regression models and machine learning techniques.ResultsA random forest regression model outnumbered other regression models resulting in a correlation of 0.739 between true and predicted UPDRS values.ConclusionsPD-patients’ motor affection can be extrapolated from sEMG data during a simple tapping task. In the future, such records could help determine the need for medication changes in telemedicine applications.SignificanceOur findings support the utility of wearables to detect Parkinson's symptoms and could help in developing tailored therapies in the future.     

Comparison of clinical outcomes with left unilateral and sequential bilateral Transcranial Magnetic Stimulation (TMS) treatment of major depressive disorder in a large patient registry

BackgroundIt has been suggested that sequential bilateral (SBL) TMS, combining high frequency, left dorsolateral prefrontal cortex (DLPFC) stimulation and low frequency, right DLPFC stimulation, is more effective than unilateral TMS.ObjectiveTo contrast treatment outcomes of left unilateral (LUL) and SBL protocols.MethodsRegistry data were collected at 111 practice sites. Of 10,099 patients, 3,871 comprised a modified intent-to-treat (mITT) sample, defined as a primary MDD diagnosis, age ≥18, and PHQ-9 completion before TMS and at least one PHQ-9 assessment after baseline. The mITT sample received high frequency (10 Hz) LUL TMS exclusively (N = 3,327) or SBL TMS in at least 90% of sessions (N = 544). Completers (N = 3,049) were responders or had received ≥20 sessions and had an end of acute treatment PHQ-9 assessment. To control for site effects, a Matched sample (N = 653) included Completers at sites that used both protocols. To control for selection bias, the SBL group was also compared to a Restricted LUL group, drawn from sites where no patient switched to SBL after substantial exposure to LUL TMS. Secondary analyses were conducted on CGI-S ratings.ResultsThe LUL group had superior outcomes compared to the SBL group for multiple PHQ-9 and CGI-S continuous and categorical measures in the mITT, Completer and Matched samples, including in the specified primary analyses. However, outcome differences were not observed when comparing the Restricted LUL and SBL groups. Within SBL protocols, the LUL-RUL order had superior outcomes compared to the RUL-LUL order in all CGI-S, but not PHQ-9, measures.ConclusionsWhile limited by the naturalistic design, there was no evidence that SBL TMS was superior to LUL TMS. The sequential order of RUL TMS followed by LUL TMS may have reduced efficacy compared to LUL TMS followed by RUL TMS.     

Neuroimaging the menstrual cycle: A multimodal systematic review

Increasing evidence indicates that ovarian hormones affect brain structure, chemistry and function of women in their reproductive age, potentially shaping their behavior and mental health. Throughout the reproductive years, estrogens and progesterone levels fluctuate across the menstrual cycle and can modulate neural circuits involved in affective and cognitive processes. Here, we review seventy-seven neuroimaging studies and provide a comprehensive and data-driven evaluation of the accumulating evidence on brain plasticity associated with endogenous ovarian hormone fluctuations in naturally cycling women (n = 1304). The results particularly suggest modulatory effects of ovarian hormones fluctuations on the reactivity and structure of cortico-limbic brain regions. These findings highlight the importance of performing multimodal neuroimaging studies on neural correlates of systematic ovarian hormone fluctuations in naturally cycling women based on careful menstrual cycle staging.