Neurons In Subjects Research Articles

Systemic Exosomal Delivery of shRNA Minicircles Prevents Parkinsonian Pathology.

The development of new therapies to slow down or halt the progression of Parkinson's disease is a health care priority. A key pathological feature is the presence of alpha-synuclein aggregates, and there is increasing evidence that alpha-synuclein propagation plays a central role in disease progression. Consequently, the downregulation of alpha-synuclein is a potential therapeutic target. As a chronic disease, the ideal treatment will be minimally invasive and effective in the long-term. Knockdown of gene expression has clear potential, and siRNAs specific to alpha-synuclein have been designed; however, the efficacy of siRNA treatment is limited by its short-term efficacy. To combat this, we designed shRNA minicircles (shRNA-MCs), with the potential for prolonged effectiveness, and used RVG-exosomes as the vehicle for specific delivery into the brain. We optimized this system using transgenic mice expressing GFP and demonstrated its ability to downregulate GFP protein expression in the brain for up to 6weeks. RVG-exosomes were used to deliver anti-alpha-synuclein shRNA-MC therapy to the alpha-synuclein preformed-fibril-induced model of parkinsonism. This therapy decreased alpha-synuclein aggregation, reduced the loss of dopaminergic neurons, and improved the clinical symptoms. Our results confirm the therapeutic potential of shRNA-MCs delivered by RVG-exosomes for long-term treatment of neurodegenerative diseases.

Asymmetric Changes in Limbic Cortex and Planum Temporale in Patients with Alzheimer Disease.

There are several cortical areas related to the limbic system that form the output from the hippocampal formation whose cellular and morphological features are important for the onset and progression of AD. We hypothesized that there would be a significant difference in the size of cortical pyramidal neurons and that there would also be a hemispheric asymmetry between Alzheimer disease patients and controls. These differences would potentially be accompanied by an increase in the numbers of Fluoro-Jade B-positive degenerating cortical neurons and a corresponding decrease in the numbers of DAPI-stained cortical neuronal nuclei in subjects with AD compared to controls. Such changes could potentially be used as another marker in postmortem neuropathological diagnosis of AD. We measured absolute numbers of DAPI and Fluoro-Jade B stained cells in five cortical areas of the limbic system and four subareas of planum temporale in the post-mortem brains of subjects with Alzheimer disease. We also measured the size of pyramidal neurons in layer III in the five cortical areas of the limbic system in these subjects. All measurements were performed separately for the left and right hemisphere in order to identify asymmetries between the two hemispheres. We observed a significant decrease in numbers of DAPI stained cells in layers IV-VI of the anterior cingulate gyrus on the right side, in layers I-III of the posterior cingulate gyrus on the left side, in layers IV-VI in the transition region from superior temporal gyrus into planum temporale on the right and in layers IV-VI in the transition from planum temporale to insular cortex on the left. We also observed a significant increase in the numbers of Fluoro-Jade stained cells in layers I-III of the anterior cingulate gyrus and in layers I-III on the left and layers IV-VI of the right gyrus of Heschl. Shortening of the size of layer III pyramidal neurons in subjects with Alzheimer´s disease was found in the anterior cingulate gyrus on the right, in the posterior cingulate gyrus and entorhinal cortex on the left and on the right in the parahippocampal gyrus. Our study demonstrates asymmetries in different cortical regions of the temporal lobe that can be used as another marker in the postmortem diagnosis of AD.

The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity.

Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the increased presence of TDP-43 in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here, we have found that TDP-43 accumulates in mitochondria in neurons of subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. Within mitochondria, wild type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunit ND3 and ND6, impair their expression and specifically cause complex I disassembly. Suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose targeting TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.

Mitochondrial dysfunction in iPSC‐derived neurons in subjects with Chronic Mountain Sickness

Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of the high altitude population (more than 140 million highlanders) during extended living over 2500m. Patients with CMS suffer from severe hypoxemia, erythrocytosis and neurologic manifestations including migraine, headache, mental fatigue, confusion, and memory loss. The only therapy, which is inadequate, is periodic phlebotomy. By understanding the mechanisms of CMS neuropathology, we wish to be able to develop better therapeutic strategies, not only for CMS but also for those diseases that are relevant at the sea level as well.In the current study, we used induced pluripotent stem cells (iPSCs)‐derived neurons from subjects with CMS and others without any evidence of CMS (non‐CMS) living at the same altitude, as a model to study CMS in vitro. We noticed that CMS neurons are more sensitive to the culture environment than non‐CMS, with more blebbing or beadings of dendrites after 3 weeks in culture. Although intracellular ATP level is significantly decreased in the CMS group, there was no difference in LDH release between the two groups. Transmission electron microscopic images illustrated that CMS neurons have a decreased mitochondrial volume density, cristae and mitochondrial length. Real‐time PCR analysis confirmed that CMS neurons have 1) decreased mitochondrial biogenesis gene such as PGC1 and increased mitophagy genes including PARKIN and PINK; 2) decreased fission and fusion genes including DRP1, FIS, OPA, and MFN2, as well as 3) many altered nuclear and mitochondrial gene including UCP2, ANT1, VDAC, BCL2‐XL, NMNAT1, and VEGF, suggesting the present of mitochondrial dysfunction in CMS neurons. Within these genes, NMNAT1, a central enzyme of NAD biogenesis, attracts attention because overexpression of NMNAT1 is believed to be neuroprotective in neuronal morphogenesis. Decreased NAD level, due to a down‐regulation of NMNAT1, has been shown to disrupt the nuclear‐mitochondrial communication and lead to mitochondrial dysfunction and render cells in a pseudohypoxic state under normoxia. Thus, we speculate that a similar phenomenon takes place in CMS neurons; indeed we have confirmed that both NMNAT1 gene expression and NAD level are lower in CMS neurons as compared to non‐CMS neurons. We conclude that a decreased NAD level might be one of reasons for mitochondrial dysfunction and results in a vulnerable survival phenotype in CMS neurons.Support or Funding Informationsupported by NIH 5P01HL098053

Sex and laterality differences in parkinsonian impairment and transcranial ultrasound in never-treated schizophrenics and their first degree relatives in an Andean population

We tested the hypothesis that loss of substantia nigra neurons in subjects at risk of schizophrenia (1), as reflected by midbrain hyperechogenicity (2) and parkinsonian motor impairment (3), is asymmetric and influenced by sex. We evaluated 62 subjects with never-treated chronic schizophrenia, 80 of their adult, unaffected first degree relatives and 62 healthy controls (matched by sex and age to the cases), part of an Andean population of Northern Argentina. Parkinsonism was scored blindly using UPDRS-3 (Unified Parkinson's Disease Rating Scale) on videotaped exams by 2 independent raters. Transcranial ultrasound was performed by an expert sonographist blind to subject condition with a 2.5MHz transducer through a temporal bone window. Quantification of echogenic area was carried out on saved images by a different evaluator. We found a significant difference in parkinsonian motor impairment between patients, their relatives as well as controls. All three groups showed worse parkinsonism on the left side than the right, corresponding with increased echogenicity on the right substantia nigra compared with the left. Females had significantly more right echogenicity than males, and patients and unaffected relatives were significantly more echogenic than controls on that side. On the left, only female patients had significant echogenicity. Our data supports the notion that unaffected relatives of schizophrenic subjects have increased parkinsonism and concomitant brainstem abnormalities which may represent a vulnerability to the disease. Both motor and brainstem abnormalities are asymmetric and influenced by sex.

Molecular Profiles of Parvalbumin-Immunoreactive Neurons in the Superior Temporal Cortex in Schizophrenia

Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder.

Morphometric Analysis of Thoracic Ganglion Neurons in Subjects with and without Primary Palmar Hyperhidrosis

Hyperhidrosis (HH) is a disease whose physiopathology remains poorly understood and that adversely affects quality of life. There is no morphologic study that includes an adequate control group that allows for comparison of the ganglion of HH to those of normal individuals. The purpose of study was to analyze morphologic and morphometric characteristics of the ganglion from patients with HH and normal individuals (organ donators). This was a transversal study. The sympathetic thoracic ganglia were obtained from 2 groups of patients. Group PH (palmar hyperhidrosis), 40 patients with palmar HH submitted to surgery by video-assisted thoracoscopy, and group C (control group), 14 deceased individuals (control group of organ donators) without any history of HH. The third left sympathetic thoracic ganglion was resected in all patients. We observed higher number of cells in the PH group than in the control group (14.25 + 3.81 vs. 10.65 + 4.93) with P = 0.007; the mean percentage of ganglion cells stained by caspases-3 in the PH group was significantly greater than that of the C group (2.37 + 0.79 vs. 0.77 + 0.28) with P < 0.001; the mean value of area of collagen in the PH group was 0.80 IQ (0.08-1.87), and in the control group it was 2.36 IQ (0.49-5.98) with P = 0.061. Subjects with primary palmar HH have a higher number of ganglion cells within the ganglion and a higher number of cells in apoptosis. Also, the subjects of PH group have less collagen in the sympathetic ganglion when compared with the control group, but not statistically significant.

Convergent Replication of Mouse Synthetic Prion Strains

Prion diseases are neurodegenerative disorders characterized by the aberrant folding of endogenous proteins into self-propagating pathogenic conformers. Prion disease can be initiated in animal models by inoculation with amyloid fibrils formed from bacterially derived recombinant prion protein. The synthetic prions that accumulated in infected organisms are structurally distinct from the amyloid preparations used to initiate their formation and change conformationally on repeated passage. To investigate the nature of synthetic prion transformation, we infected mice with a conformationally diverse set of amyloids and serially passaged the resulting prion strains. At each passage, we monitored changes in the biochemical and biological properties of the adapting strain. The physicochemical properties of each synthetic prion strain gradually changed on serial propagation until attaining a common adapted state with shared physicochemical characteristics. These results indicate that synthetic prions can assume multiple intermediate conformations before converging into one conformation optimized for in vivo propagation.

The chandelier neuron in schizophrenia

Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABA(A) receptor α2 subunit is increased in postsynaptic AIS. These alterations are most marked in cortical layers 2-3. In addition, other determinants of the function of chandelier cell-pyramidal neuron synapses, such as ankyrin-G (which regulates the recruitment of sodium channels to the AIS), are also selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia. Each of these components of chandelier cell-pyramidal neuron connectivity exhibits distinctive developmental trajectories in the primate DLPFC, suggesting that disturbances in these trajectories could contribute to the pathogenesis of schizophrenia. Recent findings that inputs from neocortical chandelier neurons are excitatory provide new ideas about the role of this circuitry in the pathophysiology of cortical dysfunction in schizophrenia.

Compensating for Alzheimer lesions

Although there have been meaningful advances in our understanding of Alzheimer disease (AD) pathogenesis, we still do not understand the exact reasons why some individuals develop dementia while others remain normal. This mystery is addressed in this issue of Neurology ® by Iacono et al.1 Iacono et al. use sophisticated stereologic techniques to describe morphologic changes in neurons of subjects with asymptomatic AD lesions compared with those who died with mild cognitive impairment (MCI) or cognitively normal individuals with no plaque and tangle pathology. They confirmed that CA1 neurons (and neuronal subparts including the cell body, nucleus, and nucleolus) in subjects with compensated AD lesions (i.e., subjects who were still cognitively normal) were larger than those of control subjects or individuals with MCI, supporting the notion that neuronal hypertrophy in this important hippocampal subregion is associated with a biologic process that protects against cognitive impairment. Pondering the relationship between neuronal …

Selective Alterations in Postsynaptic Markers of Chandelier Cell Inputs to Cortical Pyramidal Neurons in Subjects with Schizophrenia

Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (dlPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. To understand the nature and functional significance of these alterations, we determined the density, laminar distribution and length of AIS immunoreactive for ankryin-G and βIV spectrin, two proteins involved in the regulation of synapse structure and ion channel clustering at AIS, in dlPFC area 46 from 14 matched triads of subjects with schizophrenia or major depressive disorder (MDD) and normal comparison subjects. The density of ankyrin-G-immunoreactive (IR) AIS in the superficial, but not in the deep, cortical layers was significantly decreased by 15-19% in the subjects with schizophrenia relative to the other subject groups. In contrast, no group differences were present in the density of βIV spectrin-IR AIS. The length of labeled AIS did not differ across subject groups for either ankyrin-G or βIV spectrin. The density of ankyrin-G-IR AIS was not altered in the dlPFC of macaque monkeys chronically exposed to antipsychotic medications. Given the important role of ankyrin-G in the recruitment and stabilization of sodium channels and other integral membrane proteins to AIS, our findings suggest that these processes are selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia.

Non-autonomous cell death in Parkinson's disease

Parkinson's disease (PD) is a relentlessly progressive neurodegenerative disorder, characterised by symptoms of bradykinesia, rest tremor, and rigidity, due to the loss of dopamine (DA) neurons. Intracellular accumulation and aggregation of α-synuclein in Lewy bodies and neurites accompanies the loss of DA neurons. Why DA neurons degenerate and α-synuclein aggregates in patients with PD is poorly understood. Three recent articles in Nature Medicine provide important clues to the underlying degenerative process and suggest that the loss of DA neurons and the aggregation of α-synuclein is mediated, in part, by a non-cell-autonomous process. 1 Kordower JH Chu Y Hauser RA Freeman TB Olanow CW Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med. 2008; (published online Apr 6.)https://doi.org/10.1038/nm1747 Crossref PubMed Scopus (1200) Google Scholar , 2 Li JY Englund E Holton JL et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 2008; (published online Apr 6.)https://doi.org/10.1038/nm1746 Crossref Scopus (1294) Google Scholar , 3 Mendez I Vinuela A Astradsson A et al. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med. 2008; (published online Apr 6.)https://doi.org/10.1038/nm1752 Crossref PubMed Scopus (347) Google Scholar

Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation

Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.

Safety of Macugen (pegaptanib sodium) for neovascular age‐related macular degeneration (NV‐AMD). After 3 years of experience

Abstract Purpose: To evaluate the safety of Macugen in the treatment of NV‐AMD after 3 years experience in the V.I.S.I.O.N. trial. Methods: Two concurrent, multicenter, double‐masked studies included subjects with all angiographic subtypes. Macugen (0.3, 1, or 3 mg) or sham injections were given every 6 wks for 54 wks. Those initially assigned to Macugen were re‐randomized (1:1) to continue/discontinue therapy for 48 wks; sham‐treated subjects continued, discontinued, or received Macugen. At 102 wks, subjects receiving Macugen 0.3 or 1 mg continued; those receiving other treatments or who received no treatment in yr 2 were re‐randomized to 0.3 or 1 mg (1:1). Safety endpoints included AEs, deaths, and lab values. Retrospective analysis compared fundus photos for RPE and optic disc damage of subjects receiving pegaptanib and sham. Results: Macugen was well tolerated in yr 3. In the primary safety population (n=161) who received study medication in yr 3 and active treatment during yrs 1 and 2, AEs were mainly ocular (114 [71%] subjects) and mild, with no evidence of increased systemic safety signals. Among 422 subjects treated with Macugen in yr 3, regardless of previous treatment, 2 cases of endophthalmitis (0.06%/injection), 1 case of rhegmatogenous retinal detachment (0.03%/injection), and 0 cases of traumatic cataract were reported, and no evidence of new systemic safety signals was noted. No additional damage was found to the RPE or to retinal neurons in subjects receiving 0.3 mg pegaptanib vs. sham. Conclusions: Continuous treatment with Macugen over three years in patients with NV‐AMD does not confer an increased risk for ocular or systemic AEs.

5HTTLPR Polymorphism and Enlargement of the Pulvinar: Unlocking the Backdoor to the Limbic System

The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT. Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n = 11), bipolar disorder (n = 11), schizophrenia (n = 12), and control (n = 15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance. Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects. The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression.

Age-related progressive neuronal DNA damage associated with cerebral degeneration in a mouse model of accelerated senescence.

The DNA of cerebral neurons in subjects with Alzheimer's disease is extensively damaged, although the morphological features of apoptosis are absent. We investigated whether DNA is damaged in the brains of the SAMP10 strain of mouse, in which accelerated senescence is characterized by age-related cerebral atrophy and cognitive impairment. We performed quantitative terminal deoxynucleotidyl transferase-mediated digoxigenin-labeled dUTP nick end labeling (TUNEL), using paraffin sections. TUNEL positive cells increased in number in the cerebral neurons of SAMP10 mice with aging. TUNEL positive cells were widely distributed in mice at age 13-14 months, and obvious in the olfactory tubercle, anterior cingulate cortex, insular cortex, and amygdala. These TUNEL positive cells did not have the morphological features of apoptosis. Therefore, the DNA became damaged with advancing age through a mechanism other than apoptosis. SAMP10 is a useful mouse model of brain aging that mimics the progressive neuronal DNA damage associated with human neurodegenerative disorders.

In Alzheimer's Disease, Heme Oxygenase Is Coincident with Alz50, an Epitope of τ Induced by 4‐Hydroxy‐2‐Nonenal Modification

In this study, we compared the neuronal induction of the antioxidant heme oxygenase-1 (HO-1) in Alzheimer's disease with abnormalities in tau marked by antibodies recognizing either phosphorylation (AT8) or conformational change (Alz50). The epitope recognized by Alz50 shows a complete overlap with HO-1-containing neurons, but AT8 recognized these neurons as well as neurons not displaying HO-1. These findings suggest that tau phosphorylation precedes the HO-1 response and that HO-1 is coincident with the Alz50 epitope. This led us to consider whether oxidative damage plays a role in forming the Alz50 epitope. We found that 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation, reacts with normal tau and induces the Alz50 epitope in tau. It is important that the ability of HNE to create the Alz50 epitope not only is dependent on lysine residues of tau but also requires tau phosphorylation because neither methylated, recombinant, nor dephosphorylated tau reacts with HNE to create the Alz50 epitope. Supporting the in vivo relevance of this observation, endogenous paired helical filament-tau isolated from subjects with Alzheimer's disease was immunoreactive with an antibody to a stable HNE-lysine adduct, as were all vulnerable neurons in subjects with Alzheimer's disease but not in control individuals. Together, these findings support the involvement of oxidative damage early in neurofibrillary tangle formation in Alzheimer's disease and also suggest that HNE modification contributes to the generation of the tau conformation defining the Alz50 epitope. These findings provide evidence that an interplay between phosphorylation of tau and neuronal oxidative stress-induced pathology is important in the formation of neurofibrillary tangles.

Abnormal development of biceps brachii phasic stretch reflex and persistence of short latency heteronymous reflexes from biceps to triceps brachii in spastic cerebral palsy.

Co-contraction of antagonist muscles is characteristic of spasticity arising from perinatal brain damage but not in spasticity occurring after brain damage in adulthood. Such co-contraction is a normal feature of early post-natal motor development. Heteronymous, monosynaptic Group Ia projections from biceps brachii to both the antagonist triceps brachii and to other synergist and non-synergist muscles of the upper limb occur in the newborn baby and become restricted during the first 4 years to motor neurons of primarily synergistic muscles. Longitudinal and cross-sectional studies have been performed to test the hypothesis that inappropriate heteronymous excitatory projections persist in children with perinatal brain damage who develop spasticity. Subjects with spasticity, from brain damage acquired in adulthood were also studied to determine if these projections simply become unmasked as part of spasticity, independent of the age of occurrence of the brain damage. Twenty-nine healthy newborn babies and 29 at high risk for cerebral palsy, 12 of whom developed spastic quadriparesis, were studied longitudinally for 4 years. Thirty-eight subjects, aged 8-30 years, with spasticity of perinatal origin (11 hemiplegic, 11 quadriplegic, 16 with Rett syndrome) and 11 subjects with stroke in adulthood and spastic hemiplegia were also studied. The results were compared with those obtained in 372 normal subjects aged from birth to 55 years. Small taps were delivered to the tendon of biceps brachii using an electromechanical tapper. Surface EMG was recorded from biceps and triceps brachii, pectoralis major and deltoid. In the longitudinal study, those developing spastic quadriparesis showed persistent low thresholds for the homonymous phasic stretch reflex, which had abnormally short onset latencies. There was persistence of short onset heteronymous excitatory responses in triceps brachii, while a normal pattern of restriction of heteronymous responses to pectoralis major and deltoid occurred. The same pattern was observed in older subject groups with spasticity of perinatal origin. In adults with hemiplegia following stroke the threshold of the homonymous phasic stretch reflex was low, but it had a normal onset latency. There was no evidence of abnormal heteronymous excitatory responses. In conclusion, exaggerated excitatory responses to primary muscle afferent input were observed in the homonymous (biceps brachii) and antagonist (triceps brachii) motor neurons in subjects with spasticity arising from perinatal brain damage. They are likely to play an important role in the predominant co-contraction of agonist/antagonist muscles during voluntary movement observed in subjects with spastic cerebral palsy.

Primary somatosensory cortex and pain perception: Yes sir, your pain is in your head (Part I)

This Focus article proposes that the primary somatosensory cortex (SI) is the first level of conscious pain perception, treating the incoming information about pain as any other novel stimulus. The cortical processes underlying conscious pain perception are distributed in nature and are probably similar to cortical processes underlying conscious perception of other sensory modalities, like touch, hearing, or vision. In general, processes in SI are very dynamic across all somatosensory modalities, and the sensory cortices provide important inputs for motor control and performance. But SI is not the “pain center,” because it is the interaction of SI with the other pain-related cortical and subcortical areas and structures, rather than activity of SI, that results in experience of pain. So destruction of SI leads to altered pain perception and not to abolition of pain. Any discussion regarding pain perception has to address the differences between acute pain and chronic pain, because of their biological difference and because of the varying neural processes underlying each one. The most significant difference is neuroplasticity in chronic pain. Consequently, properties of SI nociceptive neurons are altered in subjects with chronic pain when compared to pain responses of SI neurons in subjects without chronic pain.

Reorganization of cortical blood flow and transcranial magnetic stimulation maps in human subjects after upper limb amputation.

1. Two complimentary techniques were used to study cortical function in six human upper limb amputees: positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) were made in subjects during limb movements to study activation of the primary motor (M1), primary somatosensory (S1), and association cortices; and electromyographic responses to transcranial magnetic stimulation (TMS) were measured in proximal upper limb muscles to assess the excitability of corticospinal neurons in subjects at rest. 2. To explore possible cortical mechanisms governing the phantom limb phenomenon, PET and TMS findings were compared between subjects with acquired, traumatic upper limb amputations (n = 3), in whom phantom limb symptoms were prominent, and congenital upper limb amputees (n = 3) without phantom limbs. 3. Paced shoulder movements were associated with significant blood flow increases in the contralateral M1/S1 cortex of both groups of amputees. In traumatic amputees, these increases were present over a wider area and were of significantly greater magnitude in the partially deafferented cortex contralateral to the amputation. In congenital amputees blood flow increases were also present over a wider area in the partially deafferented M1/S1 cortex, but their magnitude was not significantly different from that in the normally afferented M1/S1 cortex. 4. Abnormal blood flow increases also were present in the partially deafferented M1/S1 cortex of traumatic amputees during movement of the ipsilateral, intact arm. Abnormal ipsilateral M1/S1 responses were not present during movement of the intact arm in the congenital group. 5. TMS studies showed that the abnormal blood flow increases in the partially deafferented M1 cortex of traumatic amputees were associated with increased corticospinal excitability.(ABSTRACT TRUNCATED AT 250 WORDS)