Cortical activation during imagined walking for people with lower limb loss: a pilot study.

Each year in Canada, a substantial number of adults undergo limb amputation, with lower limb amputation (LLA) the most prevalent. Enhancing walking ability is crucial for optimizing rehabilitation outcomes, promoting participation, and facilitating community reintegration. Overcoming challenges during the acute post-amputation phase and sub-acute rehabilitation necessitates alternative approaches, such as motor imagery and mental practice, to maximize rehabilitation success. However, the current evidence on activation patterns using motor imagery in individuals with LLA is limited. The primary objective was to assess the feasibility of observing brain activation during imagined walking in individuals with LLA utilizing 3T functional magnetic resonance imaging (fMRI). Eight individuals with LLA and 11 control subjects participated. Consistent with representations of the lower limbs, both control and amputee groups demonstrated bilateral activation in the medial surface of the primary motor and somatosensory cortices. However, individuals with lower limb amputations exhibited significantly greater activation during imagined walking, particularly in frontal regions and the medial surface of the primary motor and supplementary motor cortices. Furthermore, the volume of activation in the bilateral primary motor cortices was higher for participants with amputations compared to controls. The protocol developed in this study establishes a foundation for evaluating the effects of a gait training program that incorporates mental imagery alongside conventional rehabilitation practices, in contrast to standard care alone. This pilot investigation holds potential to enhance our understanding of brain plasticity in individuals with LLA and pave the way for more effective rehabilitation strategies to optimize functional recovery and community reintegration.

Effects of Memantine and High Dose Vitamin D on Gait in Male APP/PS1 Alzheimer's Disease Mice Following Vitamin D Deprivation.

BACKGROUND: Altered gait is a frequent feature of Alzheimer's disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-ß and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. OBJECTIVE: Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. METHODS: Male APPswe/PS1dE9 mice were split into four groups (n = 14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups started a vitamin D-deficient diet at month 6. One group remained on this deficient diet for the rest of the study. At month 9, the other two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait was assessed using CatWalk at months 6, 9, 12, and 15. RESULTS: Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p < 0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p < 0.01), while mice treated with memantine and vitamin D did not (p = 0.21). CONCLUSION: Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD.

Effect of Memantine Treatment and Combination with Vitamin D Supplementation on Body Composition in the APP/PS1 Mouse Model of Alzheimer's Disease Following Chronic Vitamin D Deficiency.

BACKGROUND: Vitamin D deficiency and altered body composition are common in Alzheimer's disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-ß exposure and glutamate toxicity. OBJECTIVE: To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. METHODS: Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n = 14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The vitamin D-deficient group (n = 14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n = 14), while the other had both memantine and 10 IU/g vitamin D (n = 14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. RESULTS: In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p < 0.01) and absolute skeletal tissue mass (9.3% increase, p < 0.05) and volume (9.2% increase, p < 0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. CONCLUSION: Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD.

1H MR spectroscopy of the motor cortex immediately following transcranial direct current stimulation at 7 Tesla.

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that may modulate cortical excitability, metabolite concentration, and human behaviour. The supplementary motor area (SMA) has been largely ignored as a potential target for tDCS neurorehabilitation but is an important region in motor compensation after brain injury with strong efferent connections to the primary motor cortex (M1). The objective of this work was to measure tissue metabolite changes in the human motor cortex immediately following tDCS. We hypothesized that bihemispheric tDCS would change levels of metabolites involved in neuromodulation including N-acetylaspartate (NAA), glutamate (Glu), and creatine (tCr). In this single-blind, randomized, cross-over study, fifteen healthy adults aged 21-60 participated in two 7T MRI sessions, to identify changes in metabolite concentrations by magnetic resonance spectroscopy. Immediately after 20 minutes of tDCS, there were no significant changes in metabolite levels or metabolite ratios comparing tDCS to sham. However there was a trend toward increased NAA/tCr concentration (p = 0.08) in M1 under the stimulating cathode. There was a strong, positive correlation between the change in the absolute concentration of NAA and the change in the absolute concentration of tCr (p<0.001) suggesting an effect of tDCS. Both NAA and creatine are important markers of neurometabolism. Our findings provide novel insight into the modulation of neural metabolites in the motor cortex immediately following application of bihemispheric tDCS.

Metabolite and functional profile of patients with cervical spondylotic myelopathy.

OBJECTIVE The goal of this study was to compare the recovery of neuronal metabolism and functional reorganization in the primary motor cortex (M1) between mild and moderate cervical spondylotic myelopathy (CSM) following surgical intervention. METHODS Twenty-eight patients with CSM underwent 3-T MRI scans that included spectroscopy and functional MRI, before surgery and 6 months postsurgery. The classification of severity was based on the modified Japanese Orthopaedic Association questionnaire. Mild and moderate myelopathy were defined by modified Japanese Orthopaedic Association scores > 12 of 18 (n = 15) and 9-12 (n = 13), respectively. Ten healthy control subjects underwent 2 MRI scans 6 months apart. Metabolite levels were measured in the M1 contralateral to the greater deficit side in patients with CSM and on both sides in the controls. Motor function was assessed using a right finger-tapping paradigm and analyzed with BrainVoyager QX. RESULTS Patients with mild CSM had a lower preoperative N-acetylaspartate to creatine (NAA/Cr) ratio compared with moderate CSM, suggesting mitochondrial dysfunction. Postsurgery, NAA/Cr in moderate CSM decreased to the levels observed in mild CSM. Preoperatively, patients with mild CSM had a larger volume of activation (VOA) in the M1 than those with moderate CSM. Postoperatively, the VOAs were comparable between the mild and moderate CSM groups and had shifted toward the primary sensory cortex. CONCLUSIONS The NAA/Cr ratio and VOA size in the M1 can be used to discriminate between mild and moderate CSM. Postsurgery, the metabolite profile of the M1 did not recover in either group, despite significant clinical improvement. The authors proposed that metabolic impairment in the M1 may trigger the recruitment of adjacent healthy cortex to achieve functional recovery.

Cervical Spondylotic Myelopathy: Metabolite Changes in the Primary Motor Cortex after Surgery.

Purpose To characterize longitudinal metabolite alterations in the motor cortex of patients with cervical spondylotic myelopathy (CSM) by using proton magnetic resonance (MR) spectroscopy and to evaluate white matter integrity with diffusion-tensor imaging in patients who are recovering neurologic function after decompression surgery. Materials and Methods Informed written consent was obtained for all procedures and the study was approved by Western University's Health Sciences Research Ethics Board. Twenty-eight patients with CSM and 10 healthy control subjects were prospectively recruited and underwent two separate 3-T MR imaging examinations 6 months apart. Patients with CSM underwent surgery after the first examination. N-acetylaspartate (NAA), an indicator of neuronal mitochondrial function, normalized to creatine (Cr) levels were measured from the motor cortex contralateral to the greater functional deficit side in the patient group and on both sides in the control group. Fractional anisotropy and mean diffusivity were measured by means of diffusion-tensor imaging in the white matter adjacent to the motor and sensory cortices of the hand and the entire cerebral white matter. Clinical data were analyzed by using Student t tests. Results In patients with CSM, NAA normalized to Cr (NAA/Cr) levels were significantly lower 6 months after surgery (1.48 ± 0.08; P < .03) compared with preoperative levels (1.73 ± 0.09), despite significant improvement in clinical questionnaire scores. Fractional anisotropy and mean diffusivity were the same (P > .05) between the patient and control groups in all measured regions at all time points. Conclusion NAA/Cr levels decreased in the motor cortex in patients with CSM 6 months after successful surgery. Intact white matter integrity with decreased NAA/Cr levels suggests that mitochondrial metabolic dysfunction persists after surgery. © RSNA, 2016 Online supplemental material is available for this article.

Illness versus substance use effects on the frontal white matter in early phase schizophrenia: A 4Tesla (1)H-MRS study.

OBJECTIVE: Young adults with early phase schizophrenia often report a past or current pattern of illicit substance use and/or alcohol misuse. Still, little is known about the cumulative and separate effects of each stressor on white matter tissue, at this vulnerable period of brain development. METHODS: Participants involved 24 healthy controls with a past or current history of sustained illicit drug use and/or alcohol misuse (users), 23 healthy controls without such history (normative data), and 27 users with early phase schizophrenia. (1)H-MRS data were acquired from a large frontal volume encompassing 95% of white matter, using a 4Tesla scanner (LASER sequence, TR/TE 3200/46ms). RESULTS: Reduced levels of choline-containing compounds (Cho) were specific to the effect of illness (Cohen's d=0.68), with 22% of the variance in Cho levels accounted for by duration of illness. Reduced levels of myoInositol (d=1.10) and creatine plus phosphocreatine (d=1.07) were specific to the effects of illness plus substance use. Effect of substance use on its own was revealed by reductions in levels of glutamate plus glutamine (d=0.83) in control users relative to normative data. CONCLUSIONS: The specific effect of illness on white matter might indicate a decreased synthesis of membrane phospholipids or alternatively, reduced membrane cellular density. In terms of limitations, this study did not include patients without a lifetime history of substance use (non-users), and the specific effect of each substance used could not be studied separately.

Vitamin D-related changes in intracranial volume in older adults: a quantitative neuroimaging study.

OBJECTIVES: Vitamin D is involved in skeletal and brain health. Recently, serum 25-hydroxyvitamin D (25OHD) concentration was found to be inversely correlated with intracranial volume in younger adults. Since hypovitaminosis D is most common in older adults, our objective was to determine whether this inverse correlation between 25OHD concentration and intracranial volume also occurred in older adults. STUDY DESIGN: Cross-sectional study. MAIN OUTCOME MEASURES: One hundred and ten Caucasian older community-dwellers (mean, 71.7±5.7 years; 45.5% female) received a blood test and an MRI of the brain at the same period. The intracranial volume and the subvolumes of cerebrospinal fluid, total brain, infratentorial brain, supratentorial brain, total white matter, total gray matter, cortical gray matter and subcortical gray matter were measured using FreeSurfer volumetry on T1-weighted images. Vitamin D insufficiency was defined as serum 25OHD<50nmol/L. Age, gender, body mass index, education level, use of vitamin D supplements, season of evaluation, serum concentrations of calcium and thyroid stimulating hormone were used as covariables in the analysis. RESULTS: We found that participants with vitamin D insufficiency (n=41) had greater intracranial volume than those without (1555.0±1379.2cm(3) versus 1488.0±167.4cm(3), P=0.033). Serum 25OHD concentration was cross-sectionally associated with decreased intracranial volume in mm(3) (unadjusted ß=-1194.4, P=0.028), even after adjustment for covariables (adjusted ß=-994.3, P=0.048). We found an inverse correlation of serum 25OHD with intracranial volume (r=-0.21, P=0.028) and the volume of white matter (r=-0.20, P=0.033). The other subvolumes did not correlate with serum 25OHD concentration. CONCLUSIONS: Serum 25OHD concentration was independently and inversely associated with intracranial volume in older adults.

Vitamin D and caudal primary motor cortex: a magnetic resonance spectroscopy study.

BACKGROUND: Vitamin D is involved in brain physiology and lower-extremity function. We investigated spectroscopy in a cohort of older adults to explore the hypothesis that lower vitamin D status was associated with impaired neuronal function in caudal primary motor cortex (cPMC) measured by proton magnetic resonance spectroscopic imaging. METHODS: Twenty Caucasian community-dwellers (mean±standard deviation, 74.6±6.2 years; 35.0% female) from the 'Gait and Brain Study' were included in this analysis. Ratio of N-acetyl-aspartate to creatine (NAA/Cr), a marker of neuronal function, was calculated in cPMC. Participants were categorized according to mean NAA/Cr. Lower vitamin D status was defined as serum 25-hydroxyvitamin D (25OHD) concentration <75 nmol/L. Age, gender, number of comorbidities, vascular risk, cognition, gait performance, vitamin D supplements, undernourishment, cPMC thickness, white matter hyperintensities grade, serum parathyroid hormone concentration, and season of evaluation were used as potential confounders. RESULTS: Compared to participants with high NAA/Cr (n = 11), those with low NAA/Cr (i.e., reduced neuronal function) had lower serum 25OHD concentration (P = 0.044) and more frequently lower vitamin D status (P = 0.038). Lower vitamin D status was cross-sectionally associated with a decrease in NAA/Cr after adjustment for clinical characteristics (ß = -0.41, P = 0.047), neuroimaging measures (ß = -0.47, P = 0.032) and serum measures (ß = -0.45, P = 0.046). CONCLUSIONS: Lower vitamin D status was associated with reduced neuronal function in cPMC. These novel findings need to be replicated in larger and preferably longitudinal cohorts. They contribute to explain the pathophysiology of gait disorders in older adults with lower vitamin D status, and provide a scientific base for vitamin D replacement trials.

Thalamic cramplike pain.

IMPORTANCE: We describe a case of cramplike pain after a left thalamic ischemic stroke, a neglected type of central post-stroke pain and we describe its neuroanatomical correlates. OBSERVATIONS: A 68-year-old right-handed man presented with right arm, leg, and flank cramplike pain noted upon awakening. Neurological examination was normal, with no evidence of objective sensory abnormalities. Because of the nature of the pain and the preserved sensory function, we first did not consider stroke as a potential cause, and suspected that pain was related to the combined effect of intense physical exercising on the right side and the use of statins. Diffusion-weighted magnetic resonance imaging showed an acute ischemic infarction within the left thalamus. By registering high-resolution 3 T T1-weighted and T2-weighted magnetic resonance images to the Talairach atlas, we showed the infarction is within the border between the pulvinar and the ventral posterior medial nuclei. Brodmann's areas 3, 1, 2, 4 and 6 were identified as the cortical correlates of the ischemic lesion by diffusion tensor tractography. CONCLUSIONS AND RELEVANCE: Thalamic cramplike pain should be recognized as a type of central post-stroke pain, probably produced by lesions localized to the border between the ventral posterior and pulvinar nuclei and connected to the ipsilateral primary somatosensory cortex and primary and secondary motor cortices.

Motor cortex and gait in mild cognitive impairment: a magnetic resonance spectroscopy and volumetric imaging study.

Gait disorders are common in the course of dementia, even at the stage of mild cognitive impairment, owing to probable changes in higher levels of motor control. Since motor control message is ultimately supported in the brain by the primary motor cortex and since cortical lesions are frequent in the dementia process, we hypothesized that impairments of the primary motor cortex may explain the early gait disorders observed in mild cognitive impairment. Our purpose was to determine whether the neurochemistry of the primary motor cortex measured with proton magnetic resonance spectroscopy, and its volume, were associated with gait performance while single and dual-tasking in mild cognitive impairment. Twenty community dwellers with mild cognitive impairment, aged 76 years (11) [median (interquartile range)] (30% female) from the 'Gait and Brain Study' were included in this analysis. Gait velocity and stride time variability were measured while single (i.e. walking alone) and dual tasking (i.e. walking while counting backwards by seven) using an electronic walkway (GAITRite System). Ratios of N-acetyl aspartate to creatine and choline to creatine and cortical volume were calculated in the primary motor cortex. Participants were categorized according to median N-acetyl aspartate to creatine and choline to creatine ratios. Age, gender, body mass index, cognition, education level and subcortical vascular burden were used as potential confounders. Participants with low N-acetyl aspartate to creatine (n = 10) had higher (worse) stride time variability while dual tasking than those with high N-acetyl aspartate to creatine (P = 0.007). Those with high choline to creatine had slower (worse) gait velocity while single (P = 0.015) and dual tasking (P = 0.002). Low N-acetyl aspartate to creatine was associated with increased stride time variability while dual tasking (adjusted ß = 5.51, P = 0.031). High choline to creatine was associated with slower gait velocity while single (adjusted ß = -26.56, P = 0.009) and dual tasking (adjusted ß = -41.92, P = 0.022). Cortical volume correlated with faster gait velocity while single (P = 0.029) and dual tasking (P = 0.037), and with decreased stride time variability while single tasking (P = 0.034). Finally, the probability of exhibiting abnormal metabolite ratios in the primary motor cortex was 63% higher among participants with major gait disturbances in dual task. Those with compromised gait velocity in dual task had a 2.05-fold greater risk of having a smaller cortical volume. In conclusion, the neurochemistry and volume of the primary motor cortex were associated with gait performance while single and dual tasking. Stride time variability was mainly sensitive to neuronal function (N-acetyl aspartate to creatine), whereas gait velocity was more affected by inflammatory damage (choline to creatine) and volumetric changes. These findings may contribute to a better understanding of the higher risks of mobility decline and falls in subjects with mild cognitive impairment.

Proton magnetic resonance spectroscopy of the motor cortex in cervical myelopathy.

Alterations in motor function in cervical myelopathy secondary to degenerative disease may be due to local effects of spinal compression or distal effects related to cortical reorganization. This prospective study characterizes differences in metabolite levels in the motor cortex, specifically N-acetylaspartate, creatine, choline, myo-inositol and glutamate plus glutamine, due to alterations in cortical function in patients with reversible spinal cord compression compared with healthy controls. We hypothesized that N-acetylaspartate/creatine levels would be decreased in the motor cortex of patients with cervical myelopathy due to reduced neuronal integrity/function and myo-inositol/creatine levels would be increased due to reactive gliosis. Twenty-four patients with cervical myelopathy and 11 healthy controls underwent proton-magnetic resonance spectroscopy on a 3.0 Tesla Siemens Magnetom Tim Trio MRI. Areas of activation from functional magnetic resonance imaging scans of a finger-tapping paradigm were used to localize a voxel on the side of greater motor deficit in the myelopathy group (n = 10 on right side and n = 14 on left side of the brain) and on each side of the motor cortex in controls. Neurological function was measured with the Neck Disability Index, modified Japanese Orthopaedic Association and American Spinal Injury Association questionnaires. Metabolite levels were measured relative to total creatine within the voxel of interest. No metabolite differences were detected between the right side and left side of the motor cortex in controls. The myelopathy group had significantly decreased neurological function compared with the control group (Neck Disability Index: P < 0.001 and modified Japanese Orthopaedic Association: P < 0.001). There was a significant decrease in the N-acetylaspartate/creatine metabolite ratio in the motor cortex of the myelopathy group (1.21 ± 0.07) compared with the right (1.37 ± 0.03; P = 0.01) and left (1.38 ± 0.03; P = 0.007) motor cortex in controls suggesting neuronal damage or dysfunction distal to the lesion in the spine. No difference was observed in levels of myo-inositol/creatine. Thus, cortical levels of N-acetylaspartate/creatine may be a meaningful biomarker in cervical myelopathy, indicative of neuronal damage or dysfunction.

Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers.

OBJECTIVE: This in vivo (1)H magnetic resonance spectroscopy study examined levels of glutamate, glutamine, and N-acetylaspartate in patients experiencing their first episode of schizophrenia. METHOD: Localized in vivo (1)H spectra were acquired at 4.0 T from the left anterior cingulate and thalamus of 21 never-treated patients with schizophrenia and 21 comparable healthy volunteers. RESULTS: The level of glutamine was significantly higher in the left anterior cingulate cortex and thalamus of the patients with schizophrenia than in the healthy subjects. No differences were found between groups in the levels of other metabolites in the anterior cingulate or thalamus. CONCLUSIONS: Higher than normal glutamine levels in the left anterior cingulate and thalamus provide in vivo evidence of greater than normal glutamatergic activity proposed by glutamatergic models of schizophrenia. In contrast to other studies in chronically ill patients, no differences were seen in the levels of N-acetylaspartate in either location, suggesting that the findings in patients with chronic schizophrenia may be related to the effect of medication or the progression of the illness.