Objective
This study was undertaken to better understand the high variability in response seen when treating human subjects with restorative therapies poststroke. Preclinical studies suggest that ...neural function, neural injury, and clinical status each influence treatment gains; therefore, the current study hypothesized that a multivariate approach incorporating these 3 measures would have the greatest predictive value.
Methods
Patients 3 to 6 months poststroke underwent a battery of assessments before receiving 3 weeks of standardized upper extremity robotic therapy. Candidate predictors included measures of brain injury (including to gray and white matter), neural function (cortical function and cortical connectivity), and clinical status (demographics/medical history, cognitive/mood, and impairment).
Results
Among all 29 patients, predictors of treatment gains identified measures of brain injury (smaller corticospinal tract CST injury), cortical function (greater ipsilesional motor cortex M1 activation), and cortical connectivity (greater interhemispheric M1–M1 connectivity). Multivariate modeling found that best prediction was achieved using both CST injury and M1–M1 connectivity (r2 = 0.44, p = 0.002), a result confirmed using Lasso regression. A threshold was defined whereby no subject with >63% CST injury achieved clinically significant gains. Results differed according to stroke subtype; gains in patients with lacunar stroke were best predicted by a measure of intrahemispheric connectivity.
Interpretation
Response to a restorative therapy after stroke is best predicted by a model that includes measures of both neural injury and function. Neuroimaging measures were the best predictors and may have an ascendant role in clinical decision making for poststroke rehabilitation, which remains largely reliant on behavioral assessments. Results differed across stroke subtypes, suggesting the utility of lesion‐specific strategies. ANN NEUROL 2015;77:132–145
Valid biomarkers of motor system function after stroke could improve clinical decision-making. Electroencephalography-based measures are safe, inexpensive, and accessible in complex medical settings ...and so are attractive candidates. This study examined specific electroencephalography cortical connectivity measures as biomarkers by assessing their relationship with motor deficits across 28 days of intensive therapy. Resting-state connectivity measures were acquired four times using dense array (256 leads) electroencephalography in 12 hemiparetic patients (7.3 ± 4.0 months post-stroke, age 26-75 years, six male/six female) across 28 days of intensive therapy targeting arm motor deficits. Structural magnetic resonance imaging measured corticospinal tract injury and infarct volume. At baseline, connectivity with leads overlying ipsilesional primary motor cortex (M1) was a robust and specific marker of motor status, accounting for 78% of variance in impairment; ipsilesional M1 connectivity with leads overlying ipsilesional frontal-premotor (PM) regions accounted for most of this (R(2) = 0.51) and remained significant after controlling for injury. Baseline impairment also correlated with corticospinal tract injury (R(2) = 0.52), though not infarct volume. A model that combined a functional measure of connectivity with a structural measure of injury (corticospinal tract injury) performed better than either measure alone (R(2) = 0.93). Across the 28 days of therapy, change in connectivity with ipsilesional M1 was a good biomarker of motor gains (R(2) = 0.61). Ipsilesional M1-PM connectivity increased in parallel with motor gains, with greater gains associated with larger increases in ipsilesional M1-PM connectivity (R(2) = 0.34); greater gains were also associated with larger decreases in M1-parietal connectivity (R(2) = 0.36). In sum, electroencephalography measures of motor cortical connectivity-particularly between ipsilesional M1 and ipsilesional premotor-are strongly related to motor deficits and their improvement with therapy after stroke and so may be useful biomarkers of cortical function and plasticity. Such measures might provide a biological approach to distinguishing patient subgroups after stroke.
Tobacco smoking remains one of the leading causes of preventable illness and death and is heritable with complex underpinnings. Converging evidence suggests a contribution of the polygenic risk for ...smoking to the use of tobacco and other substances. Yet, the underlying brain mechanisms between the genetic risk and tobacco smoking remain poorly understood.
Genomic, neuroimaging, and self-report data were acquired from a large cohort of adolescents from the IMAGEN study (a European multicenter study). Polygenic risk scores (PGRS) for smoking were calculated based on a genome-wide association study meta-analysis conducted by the Tobacco and Genetics Consortium. We examined the interrelationships among the genetic risk for smoking initiation, brain structure, and the number of occasions of tobacco use.
A higher smoking PGRS was significantly associated with both an increased number of occasions of tobacco use and smaller cortical volume of the right orbitofrontal cortex (OFC). Furthermore, reduced cortical volume within this cluster correlated with greater tobacco use. A subsequent path analysis suggested that the cortical volume within this cluster partially mediated the association between the genetic risk for smoking and the number of occasions of tobacco use.
Our data provide the first evidence for the involvement of the OFC in the relationship between smoking PGRS and tobacco use. Future studies of the molecular mechanisms underlying tobacco smoking should consider the mediation effect of the related neural structure.
The functional neuroanatomy and connectivity of reward processing in adults are well documented, with relatively less research on adolescents, a notable gap given this developmental period's ...association with altered reward sensitivity. Here, a large sample (n = 1,510) of adolescents performed the monetary incentive delay (MID) task during functional magnetic resonance imaging. Probabilistic maps identified brain regions that were reliably responsive to reward anticipation and receipt, and to prediction errors derived from a computational model. Psychophysiological interactions analyses were used to examine functional connections throughout reward processing. Bilateral ventral striatum, pallidum, insula, thalamus, hippocampus, cingulate cortex, midbrain, motor area, and occipital areas were reliably activated during reward anticipation. Bilateral ventromedial prefrontal cortex and bilateral thalamus exhibited positive and negative activation, respectively, during reward receipt. Bilateral ventral striatum was reliably active following prediction errors. Previously, individual differences in the personality trait of sensation seeking were shown to be related to individual differences in sensitivity to reward outcome. Here, we found that sensation seeking scores were negatively correlated with right inferior frontal gyrus activity following reward prediction errors estimated using a computational model. Psychophysiological interactions demonstrated widespread cortical and subcortical connectivity during reward processing, including connectivity between reward‐related regions with motor areas and the salience network. Males had more activation in left putamen, right precuneus, and middle temporal gyrus during reward anticipation. In summary, we found that, in adolescents, different reward processing stages during the MID task were robustly associated with distinctive patterns of activation and of connectivity.
EEG has been used to study acute stroke for decades; however, because of several limitations EEG-based measures rarely inform clinical decision-making in this setting. Recent advances in EEG ...hardware, recording electrodes, and EEG software could overcome these limitations. The present study examined how well dense-array (256 electrodes) EEG, acquired with a saline-lead net and analyzed with whole brain partial least squares (PLS) modeling, captured extent of acute stroke behavioral deficits and varied in relation to acute brain injury. In 24 patients admitted for acute ischemic stroke, 3 min of resting-state EEG was acquired at bedside, including in the ER and ICU. Traditional quantitative EEG measures (power in a specific lead, in any frequency band) showed a modest association with behavioral deficits NIH Stroke Scale (NIHSS) score in bivariate models. However, PLS models of delta or beta power across whole brain correlated strongly with NIHSS score (R(2) = 0.85-0.90) and remained robust when further analyzed with cross-validation models (R(2) = 0.72-0.73). Larger infarct volume was associated with higher delta power, bilaterally; the contralesional findings were not attributable to mass effect, indicating that EEG captures significant information about acute stroke effects not available from MRI. We conclude that 1) dense-array EEG data are feasible as a bedside measure of brain function in patients with acute stroke; 2) high-dimension EEG data are strongly correlated with acute stroke behavioral deficits and are superior to traditional single-lead metrics in this regard; and 3) EEG captures significant information about acute stroke injury not available from structural brain imaging.
Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early‐life stress in predicting psychopathology. Previous results ...suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion‐processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting‐state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE‐corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.
In 774 young European adults, we examined if child abuse and rs1360780 of the FKBP5 gene interact in predicting resting‐state functional connectivity (rsFC) between the amygdala and other areas of the salience network. An interaction was found in rsFC with the right posterior insula, driven by stronger rsFC in TT allele carriers with a history of abuse. After exposure to childhood abuse, individuals with the rs1360780 TT genotype may become more vulnerable to develop psychopathology due to altered amygdala functional connectivity.
Background. Although rehabilitation therapy is commonly provided after stroke, many patients do not derive maximal benefit because of access, cost, and compliance. A telerehabilitation-based program ...may overcome these barriers. We designed, then evaluated a home-based telerehabilitation system in patients with chronic hemiparetic stroke. Methods. Patients were 3 to 24 months poststroke with stable arm motor deficits. Each received 28 days of telerehabilitation using a system delivered to their home. Each day consisted of 1 structured hour focused on individualized exercises and games, stroke education, and an hour of free play. Results. Enrollees (n = 12) had baseline Fugl-Meyer (FM) scores of 39 ± 12 (mean ± SD). Compliance was excellent: participants engaged in therapy on 329/336 (97.9%) assigned days. Arm repetitions across the 28 days averaged 24,607 ± 9934 per participant. Arm motor status showed significant gains (FM change 4.8 ± 3.8 points, P = .0015), with half of the participants exceeding the minimal clinically important difference. Although scores on tests of computer literacy declined with age (r = −0.92; P < .0001), neither the motor gains nor the amount of system use varied with computer literacy. Daily stroke education via the telerehabilitation system was associated with a 39% increase in stroke prevention knowledge (P = .0007). Depression scores obtained in person correlated with scores obtained via the telerehabilitation system 16 days later (r = 0.88; P = .0001). In-person blood pressure values closely matched those obtained via this system (r = 0.99; P < .0001). Conclusions. This home-based system was effective in providing telerehabilitation, education, and secondary stroke prevention to participants. Use of a computer-based interface offers many opportunities to monitor and improve the health of patients after stroke.
It has not yet been determined if the commonly reported cannabis-psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders.
We examined whether the ...relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort.
PRS-Sz significantly predicted cannabis use (
= 0.027) and PLE (
= 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (
= 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects.
These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis-psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability.
Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of ...these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence.
Participants were 14 years of age and part of the IMAGEN study, a large (
= 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ).
We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region (
< 0.01, Cohen's
= -0.24), bilateral anterior and mid-cingulum (
< 0.05, Cohen's
= -0.18), right cerebellum and fusiform (
< 0.05, Cohen's
= -0.20) and left frontal superior and middle gyri (
< 0.05, Cohen's
= -0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls.
Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.
Rates of cannabis use among adolescents are high, and are increasing concurrent with changes in the legal status of marijuana and societal attitudes regarding its use. Recreational cannabis use is ...understudied, especially in the adolescent period when neural maturation may make users particularly vulnerable to the effects of Δ-9-tetrahydrocannabinol (THC) on brain structure. In the current study, we used voxel-based morphometry to compare gray matter volume (GMV) in forty-six 14-year-old human adolescents (males and females) with just one or two instances of cannabis use and carefully matched THC-naive controls. We identified extensive regions in the bilateral medial temporal lobes as well as the bilateral posterior cingulate, lingual gyri, and cerebellum that showed greater GMV in the cannabis users. Analysis of longitudinal data confirmed that GMV differences were unlikely to precede cannabis use. GMV in the temporal regions was associated with contemporaneous performance on the Perceptual Reasoning Index and with future generalized anxiety symptoms in the cannabis users. The distribution of GMV effects mapped onto biomarkers of the endogenous cannabinoid system providing insight into possible mechanisms for these effects.
Almost 35% of American 10th graders have reported using cannabis and existing research suggests that initiation of cannabis use in adolescence is associated with long-term neurocognitive effects. We understand very little about the earliest effects of cannabis use, however, because most research is conducted in adults with a heavy pattern of lifetime use. This study presents evidence suggesting structural brain and cognitive effects of just one or two instances of cannabis use in adolescence. Converging evidence suggests a role for the endocannabinoid system in these effects. This research is particularly timely as the legal status of cannabis is changing in many jurisdictions and the perceived risk by youth associated with smoking cannabis has declined in recent years.
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