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DNA Methylation Plasticity

DNA Methylation Plasticity

Does DNA methylation affect plasticity?

Methylation plays a role in a variety of bodily functions, including plasticity. The regulation of DNA methylation is essential for cells to “read” epigenetic patterns. Methylation occurs randomly in regions known as the metastable epialleles. These epigenetic patterns are then passed down to offspring during fetal development, and they will continue to be preserved through multiple generations. How genomic imprinting impacts DNA methylation and plasticity has been demonstrated in a variety of research studies.

Genomic imprinting is tremendously affected by environmental factors. By way of instance, exposure to the fungicide vinclozolin and the pesticide methoxychlor can trigger alterations in epigenetic patterns which can carry over to future generations, regardless of maintained exposure. Environmental factors may also prevent DNA methylation activity, which may cause various health issues.

Genomic Imprinting and DNA Methylation

Nutrient deficiencies required for SAMe biosynthesis and/or DNA methylation activity may lead to permanent nutritional deficits in CpG methylation. Animal research studies have demonstrated that supplements, such as folic acid, vitamin B12, choline, and betaine, during pregnancy can have a considerable, restorative impact on offspring DNA methylation activity and SAMe biosynthesis.

As mentioned above, the preservation of DNA methylation in proliferative cells and/or tissues may also be tremendously affected by nutritional deficiencies in methyl donor status and/or DNA methylation activity. As a matter of fact, DNA de-methylation, which generally develops between the ages of 34 to 68 years old, is considered to be part of the normal aging process. Human research studies have demonstrated that non-age-related alterations in DNA methylation may occur outside crucial fetal developmental stages.

In a research study published in the Lancet, researchers determined that hyperhomocysteinemia, between 16 and 100 ?mol/L plasma or serum, was considerably associated with DNA hypomethylation in humans. The research study participants were between the ages of 39 to 68 years old. Researchers believed that this occurred due to an increase in S-adenosyl homocysteine, or SAH), a powerful inhibitor of SAMe- dependent methyltransferases, including DNMTs. Induced folate deficiencies in the research study participants further worsened hyperhomocysteinemia, and folate treatment decreased plasma total homocysteine and DNA hypomethylation.

Animal research studies also demonstrated that DNA methylation may also be tremendously affected outside the critical fetal developmental stages. Dietary and lifestyle modifications may help restore methylation status. By way of instance, methionine supplements in adult rodent offspring have been demonstrated to reverse DNA methylation changes in the hippocampal glucocorticoid receptor as well as in stress responses, caused by negative maternal behaviors in early life. Moreover, betaine supplements have also been demonstrated to trigger promoter hypermethylation activity on specific genes in porcine liver.

Although the evidence is still limited, and more research studies are required to determine outcome measures, both animal and human research studies demonstrated that alterations in DNA methylation can be caused by nutrient availability, including folate, choline, vitamin B6, and vitamin B12. The outcome measures of many of these research studies suggest that multiple factors, such as food-based modulators on genomic imprinting, lifestyle, and environmental exposures, shape the overall impact on DNA methylation.

Dr Jimenez White Coat

DNA methylation has been demonstrated to tremendously affect genomic imprinting associated with nutrient deficiencies and environmental factors. Stress responses may also alter DNA methylation epigenetic patterns which are correlated with gene expression differences. According to the research studies mentioned in the following article, nutrient deficiencies and environmental factors may cause DNA methylation health issues throughout multiple generations. Understanding how DNA methylation affects plasticity is essential for individuals to continue overall health and wellness for future generations.

Dr. Alex Jimenez D.C., C.C.S.T. Insight

Smoothies and Juices for Methylation Support

While many healthcare professionals can recommend nutritional guidelines and lifestyle modifications, there are several alternative treatment options you can try for yourself at home. As described above, however, supplementation for methylation support should be correctly determined by a healthcare professional. Smoothies and juices are a fast and easy way to include all the necessary nutrients you need for methylation support in a single serving. The smoothies and juices below are part of the Methylation Diet Food Plan.

Sea Green Smoothie
Servings: 1
Cook time: 5-10 minutes
� 1/2 cup cantaloupe, cubed
� 1/2 banana
� 1 handful of kale or spinach
� 1 handful of Swiss chard
� 1/4 avocado
� 2 teaspoons spirulina powder
� 1 cup water
� 3 or more ice cubes
Blend all ingredients in a high-speed blender until completely smooth and enjoy!

Berry Bliss Smoothie
Servings: 1
Cook time: 5-10 minutes
� 1/2 cup blueberries (fresh or frozen, preferably wild)
� 1 medium carrot, roughly chopped
� 1 tablespoon ground flaxseed or chia seed
� 1 tablespoons almonds
� Water (to desired consistency)
� Ice cubes (optional, may omit if using frozen blueberries)
Blend all ingredients in a high-speed blender until smooth and creamy. Best served immediately!

Sweet and Spicy Juice
Servings: 1
Cook time: 5-10 minutes
� 1 cup honeydew melons
� 3 cups spinach, rinsed
� 3 cups Swiss chard, rinsed
� 1 bunch cilantro (leaves and stems), rinsed
� 1-inch knob of ginger, rinsed, peeled and chopped
� 2-3 knobs whole turmeric root (optional), rinsed, peeled and chopped
Juice all ingredients in a high-quality juicer. Best served immediately!

Ginger Greens Juice
Servings: 1
Cook time: 5-10 minutes
� 1 cup pineapple cubes
� 1 apple, sliced
� 1-inch knob of ginger, rinsed, peeled and chopped
� 3 cups kale, rinsed and roughly chopped or ripped
� 5 cups Swiss chard, rinsed and roughly chopped or ripped
Juice all ingredients in a high-quality juicer. Best served immediately!

Zesty Beet Juice
Servings: 1
Cook time: 5-10 minutes
� 1 grapefruit, peeled and sliced
� 1 apple, washed and sliced
� 1 whole beet, and leaves if you have them, washed and sliced
� 1-inch knob of ginger, rinsed, peeled and chopped
Juice all ingredients in a high-quality juicer. Best served immediately!

Protein Power Smoothie
Serving: 1
Cook time: 5 minutes
� 1 scoop protein powder
� 1 tablespoon ground flaxseed
� 1/2 banana
� 1 kiwi, peeled
� 1/2 teaspoon cinnamon
� Pinch of cardamom
� Non-dairy milk or water, enough to achieve desired consistency
Blend all ingredients in a high-powered blender until completely smooth. Best served immediately!

ProLon� Fasting Mimicking Diet

alanced methylation support can be achieved through proper nutrition. The ProLon� fasting mimicking diet offers a 5-day meal program which has been individually packed and labeled to serve the foods you need for the FMD in precise quantities and combinations. The meal program is made up of ready-to-eat or easy-to-prepare, plant-based foods, including bars, soups, snacks, supplements, a drink concentrate, and teas. The products are scientifically formulated and great tasting. Before starting the ProLon� fasting mimicking diet, 5-day meal program, please make sure to talk to a healthcare professional to find out if the FMD is right for you. The ProLon� fasting mimicking diet can help promote methylation support, among a variety of other healthy benefits.

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Many doctors and functional medicine practitioners may recommend higher doses of methyl donors in several patients, however, further research studies are needed to determine the proper amount of methylation supplementation. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. Your spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

Formulas for Methylation Support

Xymogen Formulas - El Paso, TX

XYMOGEN�s Exclusive Professional Formulas are available through select licensed health care professionals. The internet sale and discounting of XYMOGEN formulas are strictly prohibited.

Proudly, Dr. Alexander Jimenez makes XYMOGEN formulas available only to patients under our care.

Please call our office in order for us to assign a doctor consultation for immediate access.

If you are a patient of Injury Medical & Chiropractic Clinic, you may inquire about XYMOGEN by calling 915-850-0900.

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* All the above XYMOGEN policies remain strictly in force.

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Cutting Your Nerve Changes Your Brain | El Paso, TX.

Cutting Your Nerve Changes Your Brain | El Paso, TX.

Following upper limb peripheral nerve transection and surgical repair, some patients regain good sensorimotor function while others do not. Understanding peripheral and central mechanisms that contribute to recovery may facilitate the development of new therapeutic interventions. Plasticity following peripheral nerve transection has been demonstrated throughout the neuroaxis in animal models of nerve injury. However, the brain changes that occur following peripheral nerve transection and surgical repair in humans have not been examined. Furthermore, the extent to which peripheral nerve regeneration influences functional and structural brain changes has not been characterized. Therefore, we asked whether functional changes are accompanied by grey and/or white matter structural changes and whether these changes relate to sensory recovery? To address these key issues we (i) assessed peripheral nerve regeneration; (ii) measured functional magnetic resonance imaging brain activation (blood oxygen level dependent signal; BOLD) in response to a vibrotactile stimulus; (iii) examined grey and white matter structural brain plasticity; and (iv) correlated sensory recovery measures with grey matter changes in peripheral nerve transection and surgical repair patients. Compared to each patient�s healthy contralesional nerve, transected nerves have impaired nerve conduction 1.5 years after transection and repair, conducting with decreased amplitude and increased latency. Compared to healthy controls, peripheral nerve transection and surgical repair patients had altered blood oxygen level dependent signal activity in the contralesional primary and secondary somatosensory cortices, and in a set of brain areas known as the �task positive network�. In addition, grey matter reductions were identified in several brain areas, including the contralesional primary and secondary somatosensory cortices, in the same areas where blood oxygen level dependent signal reductions were identified. Furthermore, grey matter thinning in the post-central gyrus was negatively correlated with measures of sensory recovery (mechanical and vibration detection) demonstrating a clear link between function and structure. Finally, we identified reduced white matter fractional anisotropy in the right insula in a region that also demonstrated reduced grey matter. These results provide insight into brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.

Keywords: cortical thickness; fMRI; diffusion tensor imaging; plasticity; peripheral nerve injury
Abbreviations: BA=Brodmann area; BOLD=blood oxygen level dependent; fMRI=functional magnetic resonance imaging;
PNIr=peripheral nerve transection and surgical repair; S1=primary somatosensory cortex; S2=secondary somatosensory cortex

Introduction

Following upper limb peripheral nerve transection and surgical repair (PNIr), ?25% of patients have not returned to work 1.5 years after surgery (Jaquet et al., 2001). In addition, ?57% of patients with nerve injuries are between 16�35 years of age (McAllister et al., 1996); thus, a long life of disability and economic difficulties may accompany upper limb nerve transection. Understanding the central and peripheral ramifications of peripheral nerve injury may facilitate the development of new therapeutic strategies and intervention programs.

It is not known how the brain responds to PNIr in humans. However, animal studies have established that plasticity within the somatosensory cortex begins immediately following peripheral nerve transection, and that 1 year after complete nerve transection and surgical repair, cortical maps contain patchy, non- continuous representations of the transected and adjacent nerves (Wall et al., 1986). The mechanisms that facilitate functional plasticity are thought to include the immediate unmasking of pre-existing projections from adjacent cortical and subcortical levels, and long term sprouting of axons at multiple levels of the neuroaxis, including the primary somatosensory cortex (S1) (Florence and Kaas, 1995; Hickmott and Steen, 2005).

Human brain imaging studies have corroborated the findings from animal models with the identification of altered functional MRI activation maps due to spinal cord injury, amputation, toe- to-thumb transfer, and in patients with carpel tunnel syndrome (Lotze et al., 2001; Manduch et al., 2002; Jurkiewicz et al., 2006; Napadow et al., 2006). Furthermore, structural MRI studies have recently visualized grey and white matter changes following traumatic injuries and in diverse pathological conditions, including limb amputation and chronic pain (Apkarian et al., 2004; Draganski et al., 2006; Davis et al., 2008; Geha et al., 2008; May, 2008). Grey matter changes are thought to be related to changes in cell size, atrophy and/or loss of neurons or glia, whereas white matter changes are impacted by axonal degenera- tion and loss of myelin (Beaulieu, 2002; May, 2008).

A powerful approach to delineate mechanisms of pathology and plasticity is to combine functional and structural grey and white matter imaging techniques. We previously reported that patients with complete upper limb PNIr retained profound somatosensory deficits that persist 41.5 years following surgery (Taylor et al., 2008a). Based on these findings, we reasoned these patients would exhibit functional and structural brain changes in key somatosensory brain areas. Therefore, in this study, we hypothesized that PNIr patients would have: (i) reduced blood oxygen level dependent (BOLD) responses to vibratory stimulation of the transected nerve territory, in the region of S1 that represents the injured upper limb and in the secondary somatosensory cortex (S2); (ii) a corresponding reduction in cortical thickness in these regions of the contralesional S1 and S2; (iii) a correlation between changes in cortical thickness and psychophysical measures of somatosensory function (vibration and touch detection thresh- olds); and (iv) reduced fractional anisotropy (a measure of white matter integrity) in white matter feeding into/out of these somatosensory cortical areas.

Methods

Subjects

We recruited 27 patients with complete transection of the median and/or ulnar nerve followed by surgical repair from plastic surgeons affiliated with the University of Toronto Hand Program between June 2006 and May 2008. From this larger cohort, 14 pain-free patients (three females, 11 males; 34 ? 10 years) with complete transection of the right median and/or ulnar nerve were included in the study [to avoid confounds related to the presence of pain and laterality patients with pain (n=6) and left sided lesions (n=7) were excluded from this analysis]. All patients underwent microsurgical nerve repair at least 1.5 years prior to study enrolment (recovery time varied from 1.5 to 8 years). In addition, we recruited 14 age- and sex-matched healthy controls (3 females, 11 males; 34 ? 10 years). All subjects gave informed written consent to procedures approved by the University Health Network Research Ethics Board. All subjects were right handed (determined using the Edinburgh handedness inventory: Oldfield, 1971) and had no history of neurological injury or chronic pain (either before or after nerve transection). See Table 1 for demographic details.

nerve el paso tx.

Study Design

All subjects participated in an imaging session that included: (i) functional magnetic resonance imaging (fMRI) in response to vibrotactile stimuli applied to the right index finger (within the median nerve territory); (ii) a high-resolution anatomical scan of the whole brain, acquired for image registration and for the analysis of cortical grey matter; and (iii) two diffusion tensor imaging scans for the assessment of white matter integrity. Prior to imaging, subjects were instructed in the basic design of the experiment and reminded to remain as still as possible throughout the duration of the scan.

Subjects were free to withdraw from the study at any time. In addition, a sensory and motor assessment was performed for all subjects (Taylor et al., 2008a). As touch and vibration detection thresholds were correlated with cortical thickness a description of these methods is included below (other psychophysical measures will be reported elsewhere).

Vibration Threshold

Vibration detection thresholds were determined using a hand held Bio-Thesiometer (Bio-Medical Instrument Company, USA). The device has a 12-mm probe that was placed on the distal phalanx of the right index finger (D2). Thresholds were determined using the method of limits: the amplitude (voltage) was gradually increased until the subject indicated that they perceived the stimulus. Vibration thresholds were acquired three times and an average value was calculated. During vibration threshold testing, subjects were instructed to close their eyes and rest the back of their hand on a supportive cushion.

Mechanical Detection Threshold

Mechanical detection thresholds were determined using a standardized set of von Frey filaments (OptiHair2 Marstock Nervtest, Germany) containing 12 logarithmically spaced calibrated filaments that delivered forces from 0.25�512 mN. The contact surface diameter of all 12 filaments was ~0.4mm. Trials were conducted with the subject�s eyes closed and hands resting on a soft cushion. Probes were applied in an ascending series and subjects were required to make a response every time they felt a probe touch the right D2 fingertip. This process was repeated three times. The force for the filament that was detected in at least two of three trials was reported as that subject�s mechanical detection threshold.

Nerve Conduction Testing

Patients participated in bilateral sensory and motor nerve conduction studies at the Toronto Western Hospital electromyography (EMG) clinic. For motor nerve conduction, the stimulating electrode was placed at the wrist and elbow (separately) and the recording electrode was placed over the abductor pollicis brevis, for median nerve assessment, or the abductor digiti minimi for ulnar nerve assessment. For sensory nerve testing the recording electrode was placed at the wrist and the stimulating electrode was placed at digits D2, D3 and D5. A senior, experienced neurologist from the Toronto Western Hospital EMG Clinic (Dr Peter Ashby) reviewed all clinical assessments to deter- mine which nerves demonstrated normal/abnormal responses. As amplitude and latency measures are known to vary substantially between subjects (due to factors such as the density of innervation, the depth of the nerve and the thickness of an individual subject�s skin) (Kimura, 2001) each patient�s untransected nerve served as their own control for comparison with values from the transected side. In those patients with detectable nerve conduction responses, paired t-tests were performed to assess the difference in latency or amplitude measures between each patient�s transected and contralesional untransected nerves.

Imaging Parameters

Brain imaging data were acquired using a 3T GE MRI system fitted with an eight-channel phased array head coil. Subjects were placed supine on the MRI table and each subjects� head was padded to reduce movement. Whole-brain fMRI data was acquired using echo planar imaging (28 axial slices, field of view (FOV) = 20 x 20 cm, 64 x 64 matrix, 3.125 x 3.125 x 4mm voxels, echo time (TE) = 30 ms, repetition time (TR) = 2000 ms). The scan time was 5 min and 8 s (154 frames). During scanning, a non-painful, 12 Hz vibrotactile stimulus was applied to the distal phalanx of the right D2 using balloon diaphragms driven by compressed air (Device man- ufactured by Dr Christo Pantev; www.biomag.uni-muenster.de). Stimuli were delivered in blocks of 10s interleaved with 20s of rest, for a total of 10 blocks of stimulation and 10 blocks of rest. The first 8 s (4 TRs) of data acquired from each run were discarded to allow for fMRI signal equilibration. Subjects were instructed to keep their eyes closed throughout scanning and focus on the stimuli. A whole brain three dimensional (3D) high-resolution anatomical scan (124 sagittal slices, 24 x 24 cm FOV, 256 x� 256 matrix, 1.5 x 0.94 x 0.94 mm voxels) was acquired with a T1-weighted 3D spoiled gradient echo sequence (one signal average, flip angle = 20? , TE ?5 ms). In addition, two diffusion tensor imaging scans (38 axial slices, FOV 24 x 24 cm, 128 x 128 matrix, 1.875 x 1.875 x 3 mm voxels) were acquired along 23 directions with a b-value of 1000smm�2. Each run also contained two volumes with no diffusion weighting.

fMRI Analysis

Data were analysed using Brainvoyager QX v1.8 (Brain Innovaton, Maastricht, Netherlands). Pre-processing included: 3D motion correction, slice scan-time correction, linear trend removal, high-pass filtering (five cycles per run), and spatial smoothing with a 6mm full width at half maximum (FWHM) Gaussian kernel. fMRI data sets were interpolated to 3 x 3 x 3 mm voxels, registered to the high-resolution ana- tomical image, and normalized to standard Talairach space (Talairach and Tournoux, 1988). Voxels are reported as 1 x 1 x 1 mm. Data were analysed using the general linear model; the model was obtained by convolving the boxcar function of the time course of tactile stimulation with the standard haemodynamic response function. To identify between group differences in activation patterns a fixed effects analysis was performed with the contrasts: (i) healthy controls: stimulation 4 rest; (ii) PNIr: stimulation 4 rest; and (iii) healthy controls 4 PNIr. Activation maps were thresholded at a corrected value of P50.05 (derived from an uncorrected P50.0001 and 120mm3 contiguous voxels as previously reported: Taylor and Davis, 2009); this was also validated by running a Monte Carlo Simulation with AlphaSim application implemented in the Analysis of Functional Neuroimage (AFNI) software. This analysis included only the 11 patients that sustained transection of the right median nerve (n=9) or the right median and ulnar nerve (n = 2) (i.e. the three patients with a pure right ulnar nerve transection were not included in this analysis).

Cortical Thickness Analysis

Cortical thickness analysis was performed using Freesurfer (http:// surfer.nmr.mgh.harvard.edu); methods have been outlined in detail elsewhere (Dale et al., 1999; Fischl et al., 1999a, b; Fischl and Dale 2000). Briefly, high-resolution T1-weighted anatomical data sets were registered to the Talairach atlas (Talairach and Tournoux, 1988). This was followed by intensity normalization, skull stripping and separation of the hemispheres. Subsequently, the white/grey matter (called the white surface) and grey/CSF (called the pial surface) boundaries were identified and segmented. The distance between the white and pial surfaces was then calculated at every point in each hemisphere of the brain. To identify group differences between the 14 patients and 14 age/sex-matched controls, a general linear model analysis was performed at every point on the brain. As individual�s cortical topography is inherently heterogeneous, a 5mm FWHM spatial smoothing kernel was applied prior to statistical analysis. Data are displayed at a corrected P50.05 (derived from an uncorrected P50.0075 and 102 contiguous vertices); this was calculated by running a Monte Carlo simulation with AlphaSim. A vertex represents a point on a two dimensional sheet, and, in this study, the distance between two vertices is 0.80mm2.

As patients exhibited significant deficits in somatosensory function within the transected nerve territory, we hypothesized that measures of somatosensory function (vibration and touch detection) would correlate with cortical thickness in the contralesional post-central gyrus (primary and secondary somatosensory cortices). Therefore, we performed correlation analyses in the patient group between: (i) cortical thickness and vibration detection threshold; and (ii) cortical thickness and touch detection thresholds. One patient did not complete psychophysical assessment; therefore, this analysis included 13 PNIr patients. In addition, to determine if there was a relationship between cortical thickness and recovery time a correlation analysis was also performed between these two measures. These correlation analyses were restricted to the contralesional post-central gyrus by including a mask (taken from Freesurfer�s built in atlas) in the general linear model. A Monte Carlo simulation was performed that was restricted to the number of vertices within contralesional post-central gyrus; images are displayed with a corrected P50.05 (derived from an uncorrected P50.0075 and 68 contiguous vertices).

Diffusion Tensor Imaging Analysis

Diffusion tensor image processing was performed with DTiStudio (www.MriStudio.org) and FSLv.4.0 (www.fmrib.ox.ac.uk/fsl/). Images were first realigned with the Automatic Image Registration tool implemented in DTiStudio, using the first B0 image in the first series acquired as the template. This process corrects for subject motion and eddy-current distortion. All images were then inspected visually to assess image quality and the alignment of the separate diffusion tensor imaging runs. If an artefact was detected, the slice was removed prior to calculating the average of the two separate diffusion tensor imaging runs. Individual FA maps were calculated using the DTIFIT tool implemented in FSL. Voxel-wise statistical analysis was performed to identify group differences in the mean fractional anisotropy using Tract Based Spatial Statistics; for a full description of these methods see Smith et al. (2006). Briefly, images were non-linearly registered to a target image (MNI152), the mean image was then created from all datasets and this image was subsequently thinned to represent all tracts that were common to all subjects. Each subject�s highest fractional anisotropy values were then projected onto the skeleton by searching in white matter perpendicular to each point on the white matter skeleton. A whole-brain voxel-wise statistical analysis was then performed between groups (14PNIr and 14 healthy controls) and images were whole brain corrected at P50.05. In addition, a region of interest analysis was performed in white matter tracts adjacent to the contralateral S1, thalamus and bilateral anterior and posterior insula. These regions were chosen as they have previously been implicated in aspects of somatosensation and because they correspond with regions that were identified in the fMRI and cortical thickness analysis (CTA) group analyses. Regions of interest were drawn on the white matter skeleton as follows: (i) The contralateral S1 region of interest originated medially at the junction between the white matter skeleton of the corona-radiata and the skeleton section feeding into the post- central gyrus; terminating at the end of the tract within a given slice.

In the z direction the region of interest extended from z=49 to 57; white matter tracts supplying the hand region. (ii) The contralateral thalamus region of interest was restricted to white matter tracks surrounding the posterior and medial thalamic nuclei (nuclei involved in somatosensory function), extending from z = �1 to 4. (iii) Insular regions of interest were drawn bilaterally within white matter adjacent to the anterior and posterior insula based on criteria previously published by our lab (Taylor et al., 2008b). The region of interest extended from z = 2 to 8. Fractional anisotropy values were extracted from each of these regions of interest and a multivariate analysis of variance (MANOVA) was performed using the Statistical Package for the Social Sciences v13.0 (SPSS Inc, Chicago), which included fractional anisotropy values for all six regions of interest.

Results

Table 1 provides demographic details for study participants. All 14 patients sustained a complete transection of the right median and/or ulnar nerve followed by microsurgical repair at least 1.5 years prior to study enrolment. The time from surgery to testing ranged from 1.5 to 8 years with a mean (?SD) of 4.8 ? 3 years. Patients and controls did not (34 ? 10 years both groups; t = 0.04; P = 0.97).

Psychophysics

Vibration thresholds were calculated from all three measurements since one-way repeated measures analysis of variance (ANOVA) indicated no significant differences between the three trials [F (25, 1)=0.227, P=0.64]. Vibration and mechanical detection thresh- olds were significantly impaired in PNIr patients compared to healthy controls (vibration: t = 4.77, P50.001, Fig. 3A; mechanical: t=3.10, P=0.005, Fig. 3D).

Nerve Conduction Testing

Amplitude and latency measures obtained from each patient�s contralesional nerves were classified as normal by an experienced neurologist at the Toronto Western Hospital EMG Clinic. Nine of the 14 patients completed nerve conduction testing. Table 2 displays the average increase/decrease latency and amplitude data for sensory nerve conduction from the wrist to the abductor pollicis brevis (median) or abductor digiti minimi (ulnar) muscles and for sensory conduction from the wrist to D2 (median) and D5 (ulnar) compared to each patients uninjured contralesional nerve. Out of nine, seven patients had transections that included the median nerve. Of these seven, one patient had no detectable response during motor testing and another patient had no detectable response during sensory testing.

nerve el paso tx. In the six patients with detectable responses, motor conduction latencies were increased by 43% (t=6.2; P=0.002) and amplitudes were decreased by 38% (t=�2.6; P=0.045) when each patient�s transected nerve was compared to their non-injured side. Sensory conduction in median nerves also revealed a 26% increase in latency (t=3.9; P=0.011) and a 73% decrease in amplitude (t=�8.0; P=0.000) compared to normal contralesional nerves. In the four patients with ulnar nerve transections one patient had no detectable response during sensory nerve testing. In those patients with responses, ulnar nerve motor latencies were not significantly elevated (t = 2.8; P = 0.070); however, amplitudes were significantly
decreased by 41% (t = �5.9; P = 0.010). Sensory testing of the ulnar nerve demonstrated a 27% increase in latency (t = 4.3; P = 0.049) but no significant increase in amplitude (t = 3.5; P = 0.072).

Functional Plasticity In The Primary Somatosensory Cortex

Functional MRI maps were calculated from the 11 PNIr patients with right median nerve transections (patients with ulnar nerve transections were excluded from this analysis) and 11 age- and sex-matched healthy controls. From Fig. 1A, it is clear that PNIr patients have significantly less activation, compared to healthy controls, in a region of S1 corresponding to Brodmann area 2 (BA2) (Talairach and Tournoux, 1988) and S2 (see Table 3 for details). The average event-related responses from these regions of interest highlight the attenuated BOLD response within the patients� left BA2 and left S2 (Fig. 1B and C, respec- tively). Curiously, vibrotactile stimulation in the patients activated a more superior part of the post-central gyrus (probably BA1/3) (Talairach and Tournoux, 1988) (Fig. 1A and Table 3). An event- related average (Fig. 1D) demonstrates that healthy controls had minimal activation in this region. Furthermore, patients had significantly more activation in brain regions collectively known as the task positive network (asterisks in Fig. 1). See Table 3 for the full list of task positive brain areas activated. This network includes lateral prefrontal, lateral parietal, premotor and inferior temporal cortices (Table 3): brain areas that are activated during the performance of an attention demanding task and suppressed or inactive during rest or tasks that are not cognitively or attentionally challenging (Fox et al., 2005; DeLuca et al., 2006; Seminowicz and Davis 2007).

Reduced Grey Matter In The Primary Somatosensory Cortex Correlates With Sensory Recovery

Cortical thickness analysis in all 14 patients and 14 age/ sex-matched healthy controls revealed several loci of significant cortical thinning in the PNIr group (Fig. 2 and Table 4). Specifically, patients had a 13%�22% reduction in cortical thick- ness in the left (contralesional) S1, S2, pregenual anterior cingulate gyrus, ventrolateral prefrontal cortex and right anterior insula, anterior/posterior mid cingulate gyrus and paracentral lobule. Interestingly, the locations of grey matter thinning within the post-central gyrus coincide with the regions of reduced BOLD following vibrotactile stimulation (Table 4). Since we had prior knowledge of the patients� sensory deficits and recovery time (i.e. time since microsurgical repair), we next asked whether the patients� cortical thickness in the post-central gyrus correlated with their sensory mechanical and vibration detection thresholds, or with their recovery time. These analyses revealed a negative correlation between cortical thickness and vibration detection thresholds in a region encompassing BA1/2 and S2 (P50.001, r=?0.80 and ?0.91, for BA1/2 and S2, respectively; Fig. 3 and Table 5). In addition, mechanical detection thresholds were also negatively correlated with cortical thickness in a slightly more superior BA2 region and the same S2 region (P50.001, r = ?0.83 and ?0.85, for BA2 and S2, respectively; Fig. 3 and Table 5). However, we did not identify a significant relationship between recovery time and cortical thickness. Therefore, in the post-central gyrus cortical thinning was associated with more severe sensory deficits. However, we did not identify a significant relationship between recovery time and cortical thickness. Again, there was a correspondence between the cortical thinning in areas negatively correlated with vibratory stimuli and the regions showing group fMRI and CTA abnormalities.

White Matter Abnormalities Following Nerve Transection

To assess white matter integrity we utilized a region of interest approach to examine white matter group differences based on a priori hypotheses. Regions of interest were restricted to white matter tracts surrounding and feeding into the contralesional S1 and thalamus. In addition, we also drew regions of interest in white matter adjacent to left and right, anterior and posterior insula. The insula was chosen as it is implicated in somatosensory processing and because we identified reduced grey matter in the right anterior insular with CTA. This region of interest approach revealed that patients had significantly reduced white matter fractional anisotropy values (MANOVA including all six regions of interest) adjacent to the right anterior [F (1, 26) = 4.39, P = 0.046; Fig. 4A] and posterior insula [F (1, 26) = 5.55, P = 0.026; Fig. 4B], but there were no group differences in the white matter adjacent to the left insula (left anterior insula: P = 0.51; left posterior insula: P=0.26), thalamus (P=0.46) or S1 (P=0.46).

nerve el paso tx.Discussion

Here, we have demonstrated for the first time that there is functional plasticity and both grey and white matter structural abnormalities in several cortical areas following upper limb peripheral nerve transection and surgical repair. This plasticity may arise from incomplete peripheral nerve regeneration (peripheral cell death and/or incomplete re-myelination), as nerve conduction measures in these patients demonstrated severe abnormalities. In addition, our data demonstrate that decreased vibrotactile-evoked fMRI responses in the post-central gyrus correspond with grey matter thinning in the patient group. These results suggest that reduced BOLD responses may be facilitated by a reduction in cortical grey matter and/or a decrease in the afferent input to the post-central gyrus. In addition, cortical thickness within these same parts of the post-central gyrus negatively correlated with behavioral measures of somatosensory function. That is, increased somatosensory deficits were correlated with thinner cortex; both of which may be related to afferent input. Taken together, our data suggest that incomplete peripheral nerve regeneration contributes to somatosensory impairments, cortical grey matter atrophy and reduced fMRI activation (see Fig. 5 for a summary of these findings).

It is well known that cortical plasticity following peripheral nerve transection and surgical repair can occur throughout the CNS in non-human primates (Kaas, 1991). This plasticity is thought to be due to the unmasking of previously silent synapses or axonal sprouting into deafferented territory (Wall et al., 1986; Florence and Kaas, 1995). In the primate model, 1 year following nerve transection and surgical repair, the denervated cortex is characterized by incomplete and disorderly representations of the regenerated and adjacent (intact) nerves. This patchy representation is attributed to incomplete peripheral regeneration resulting in a partial recovery of the denervated cortical space (Kaas, 1991). To assess the extent of peripheral regeneration in our patient population we performed sensory and motor nerve conduction studies across the transected area. Our nerve conduction results demonstrate that PNIr patients have significantly decreased amplitude and increased latency in both sensory and motor nerves compared to their own untransected side. Decreased amplitude combined with increased latency is indicative of peripheral fibre loss (i.e. cell death) and/or abnormal or incomplete re-myelination following transection (Kimura, 1984). In addition, it is well established that between 20% and 50% of dorsal root ganglion neurons die following nerve transection (Liss et al., 1996). Thus, afferent cell death and incomplete regeneration can result in decreased afferent input to the cortex, which may account for ongoing sensory deficits and decreased BOLD response in BA2 and S2. Furthermore, this diminished afferent input could also account for the cortical thinning we observed in the same regions of the cortex. Sensory deprivation has been shown to cause trans- neuronal degeneration in several regions of the CNS, including the dorsal horn following sciatic nerve section (Knyihar-Csillik et al., 1989), and may involve second- and third-order neurons (Powell and Erulkar, 1962). Transneuronal degeneration is characterized by cell shrinkage and is thought to be related to decreased, or non-existent, afferent input (Knyihar-Csillik et al., 1989). Thus, cortical grey matter loss (or atrophy) could also be directly related to decreased afferent input.

nerve el paso tx.

nerve el paso tx.

nerve el paso tx.

nerve el paso tx.We also demonstrated increased activation in the post-central gyrus in a region corresponding to BA1/3 (Talairach and Tournoux, 1988). Electrophysiological, anatomical tracing and neuroimaging studies have established that for the majority of cutaneous mechanoreceptive afferents the first cortical destina- tions are BA1 and BA3b. These cytoarchitectonic brain areas each possess a somatotopic body map with small receptive fields. In addition, these areas respond to many features of tactile information, such as texture and roughness, velocity and curvature of stimuli (Bodegard et al., 2001). fMRI studies have demon- strated that activity within the somatosensory cortex is influenced by attention such that fMRI responses to tactile stimuli in S1 are increased when subjects attend to a tactile stimulus, but are atte- nuated when subjects are distracted (Arthurs et al., 2004; Porro et al., 2004). Furthermore, our patients activated a network of brain areas known as the task positive network (DeLuca et al., 2006) more than healthy controls. These brain areas are activated during attention demanding processes (Fox et al., 2005; Seminowicz and Davis, 2007). Together, these findings imply that patients must attend to the stimulus more than controls because of their impaired sensory input. This increased attention may also account for the increased activation in BA1/3b. Of course, the increased activation in BA1/3b may also reflect plasticity that is unrelated to attentional load.

nerve el paso tx.

nerve el paso tx.

nerve el paso tx.BA2 and S2 both receive projections from BA1/3b and also from distinct parts of the ventroposterior thalamic complex (Pons et al., 1985; Friedman and Murray, 1986). Both of these brain areas have large, often multi-digit (BA2) or bilateral (S2) receptive fields (Pons et al., 1985; Iwamura et al., 2002). Based on ana- tomical projections and neuronal response properties, hierarchical processing of tactile information has been demonstrated from BA1/3b to BA 2 (Kaas et al., 2002). In addition, electrophysiolo- gical studies in macaques (Pons et al., 1987) and magnetoence- phalography data acquired in humans, suggest that serial processing of tactile inputs occurs from S1 to S2 in higher primates (Frot and Mauguiere 1999; Disbrow et al., 2001). Several studies have demonstrated that BA2 is preferentially activated by shape and curvature (Bodegard et al., 2001), while S2 may be involved in tactile learning (Ridley and Ettlinger 1976; Murray and Mishkin, 1984), supporting the notion that these brain areas are involved in higher-order somatosensory processing. Our psychophysical assessment demonstrated that patients were significantly impaired at the detection of simple tactile stimuli, and in the Shape Texture Identification test 1.5 years after surgery (Taylor et al., 2008a). This latter test assesses a patient�s ability to recognize character- istics of an object while actively exploring a shape or texture, requiring the integration of sensory information across regions of the body (Rosen and Lundborg, 1998). Taken together, one inter- pretation of our data is that PNIr patients attend more to the vibrotactile stimulus, leading to increased activation of the task positive network and BA1/3. However, in these patients, our data imply that higher-order processing areas, such as BA2 and S2, did not receive tactile information, which, in turn, may result in cortical thinning and reduced BOLD responses.

The insula is thought to play a role in integrating multimodal information important for sensorimotor, emotional, allostatic/ homeostatic and cognitive functions (Devinsky et al., 1995; Critchley, 2004; Craig, 2008) and has been designated a limbic sensory cortex (Craig, 2008). Several studies have reported insular activation in response to tactile stimulation (Gelnar et al., 1998;

Downar et al., 2002) and anatomical tracing studies in primates have demonstrated that the insula is reciprocally connected to frontal, parietal and temporal lobes (Augustine, 1996). In our patients, the right anterior insula was the only cortical area that demonstrated significant cortical thinning in conjunction with reduced fractional anisotropy values in the adjacent white matter, suggesting that the cortical thinning within this region is associated with a loss of fibres projecting to or from this structure. The right anterior insula has been implicated in interoception as it is situated to integrate homeostatic input from the body with motivational, emotional and social conditions (Craig, 2008). Furthermore, Critchley et al. (2004) reported a correlation between interoceptive abilities and the grey matter volume of the right anterior insula. Given our finding that the patients have decreased grey matter in the right anterior insula, it would be of interest to assess interoceptive capabilities following peripheral nerve injury in a future study.

Taken together, we have demonstrated for the first time that functional and structural alterations are present in the human cerebral cortex 1.5 years after a complete transection of an upper limb peripheral nerve that was microsurgically repaired. In addition, nerve conduction measures indicate incomplete peripheral regeneration in these patients. Furthermore, we show that cortical thickness is related to psychophysical measures of recovery, in that thinner cortex within BA2 and S2 was associated with poorer somatosensory function. These data suggest that the reestablishment of normal functional activation maps is directly associated with the successful regeneration of peripheral afferents.

Keri S. Taylor,1,2 Dimitri J. Anastakis2,3,4 and Karen D. Davis1,2,3

1 Division of Brain, Imaging and Behaviour � Systems Neuroscience, Toronto Western Research Institute, University Health Network, Toronto, Canada M5T258
2 Institute of Medical Science, University of Toronto, Canada
3 Department of Surgery, University of Toronto, Canada
4 Clinical Studies Resource Centre, Toronto Western Research Institute, University Health Network, Toronto, Canada M5T2S8

Correspondence to: Karen D. Davis, Ph.D.,
Division of Brain, Imaging and Behaviour � Systems Neuroscience, Toronto Western Research Institute,
Toronto Western Hospital,
University Health Network,
Room MP14-306, 399 Bathurst Street,
Toronto, Ontario,
Canada M5T 2S8
E-mail: kdavis@uhnres.utoronto.ca

Acknowledgements

The authors thank Mr. Geoff Pope, Dr. Adrian Crawley, Mr. Eugene Hlasny and Mr. Keith Ta for expert technical assistance. The authors would like to thank Dr. Peter Ashby and Mr. Freddy Paiz from the Toronto Western Hospital EMG Clinic for conduct- ing the nerve conduction tests and for providing expert assess- ment of the findings. The authors also thank Drs Dvali, Binhammer, Fialkov and Antonyshyn for collaborating with this project. Dr. Davis is a Canada Research Chair in Brain and Behaviour (CIHR MOP 53304).

Funding

The Physicians� Services Incorporated and a joint seed grant from the University of Toronto Centre for the Study of Pain/ AstraZeneca.

Supplementary material

Supplementary material is available at Brain online.

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Close Accordion

Epigenetic Influences On Brain Development And Plasticity

Epigenetic Influences On Brain Development And Plasticity

Epigenetic: A fine interplay exists between sensory experience and innate genetic programs leading to the sculpting of neuronal circuits during early brain development. Recent evidence suggests that the dynamic regulation of gene expression through epigenetic mechanisms is at the interface between environmental stimuli and long lasting molecular, cellular and complex behavioral phenotypes acquired during periods of developmental plasticity. Understanding these mechanisms may give insight into the formation of critical periods and provide new strategies for increasing plasticity and adaptive change in adulthood.

Introduction

During early development, neuronal circuits are created and connections between neurons undergo remodeling as they develop their adult functional properties in response to the surrounding environment. The adult brain loses this extraordinary plasticity. Recent findings support a key role of epigenetic factors in mediating the effects of sensory experience on site-specific gene expression, synaptic transmission, and behavioral phenotypes. Here we review recent evidence implicating multiple epigenetic mechanisms in experience-dependent changes during development and discuss their role in critical period expression in the developing and adult brain.

Epigenetics: Molecular Mechanisms Of Gene Regulation

The term �epigenetic� refers to chromatin modifications which alter gene expression without affecting DNA sequence. The factors that contribute to the epigenetic regulation of transcriptional activity are numerous and include microRNA [1], DNA methylation [2,3] and post- translational modifications of nucleosomal histones [2,4]. DNA methylation refers to a chemical modification to DNA whereby cytosine is converted to 5-methylcytosine with the consequence of reduced accessibility of the DNA to transcription factors (Figure 1a�d). These modi- fications can be stable and heritable and provide a critical mechanism in cellular differentiation [3]. The process of methylation is dependent on the presence of methyl donors (provided by nutrients such as folic acid, meth- ionine and choline) and methyltransferases which med- iate either maintenance (i.e. DNMT1) or de novo DNA methylation (i.e. DNMT3). Transcriptional repression associated with DNA methylation is further sustained through methyl-binding proteins such as MeCP2 [5]. Epigenetic control of gene expression is also mediated through multiple post-translational modifications of histone proteins, including methylation, acetylation and ubiquination, which can alter the accessibility of DNA and the density of chromatin structure (Figure 1e,f). In particular, histone acetylation is associated with increased transcriptional activity whereas histone deacetylation is associated with transcriptional repression. The acetylation state of these nucleosomal proteins is controlled by the presence of histone acetyltransferases (HATs), histone deacetylases (HDACs), which are recruited by methyl-binding proteins, and by HDAC inhibitors, which effectively increase gene expression through shifting histones to an acetylated state [2,6]. The timing and degree of gene expression are controlled through these complex mechanisms, thus providing a link between single genotypes and multiple phenotypes.

Epigenetic Factors & The Influence Of Early Life Experiences

In mammalian development, the prenatal and postnatal periods are characterized by rapid changes in neuronal organization, thus providing a critical window of opportunity during which environmental experiences can lead to long-term influences on brain and behavior. There is increasing evidence for the role of epigenetic factors in mediating the relationship between these experiences and long-term outcomes. Mueller and Bale [7] have recently demonstrated decreased DNA methylation of the corticotrophin-releasing-factor (CRF) gene promotor and increased methylation of the glucocorticoid receptor (GR) exon 17 promotor region in hypothalamic tissue of adult male mice born to gestationally stressed females. These epigenetic modifications are associated with exposure to stress during the early stages of prenatal development and may involve dysregulation of placental gene expression. The nutritional environment during fetal development has likewise been demonstrated to influence growth, metabolism and brain development and there is increasing evidence that dietary levels of methyl-donors can epigenetically alter gene expression in offspring [8,9]. In rats, Lillycrop et al. [10] illustrate that GR 110 and PPARa (peroxisome proliferator-activated receptor alpha) gene promotor methylation is reduced in the hepatic tissue of offspring born to protein restricted dams whereas methylation is increased in offspring of dams whose diet is supplemented with methyl donors [10,11]. These effects may be related to DNMT1 expression, which is likewise decreased with dietary protein restriction [11]. Prenatal nutritional regulation of DNA methylation has similarly been observed in brain tissue associated with levels of DNMT1 expression [12], suggesting that in the rapid period of cell division ocurring during fetal development, the level of methyl donors can have a significant impact on transcriptional activity that is maintained into adulthood.

epigenetic el paso tx.

The role of epigenetic modification in sustaining the effects of environmental experience has also been demonstrated in the context of postnatal mother�infant interactions. Individual variations in maternal care during the immediate postpartum period in rats are associated with changes in offspring hypothalamic-pituitary-adrenal (HPA) activity, neuroendocrine systems involved in reproduction and hippocampal plasticity [13]. Analyses of levels of promotor methylation within the hippocampal GR 17 and hypothalamic ERa genes in offspring of rat dams that provide high vs. low levels of maternal care indicate that high levels of care are associated with decreased promotor methylation and thus increased gene expression [14,15]. Though the route through which these epigenetic changes are mediated is not yet clear, there is evidence for increased binding of nerve growth factor-inducible protein A (NGFI-A) to the GR exon 17 promoter amongst offspring who receive high levels of care in infancy [15] and in vitro models suggest that NGFI-A up-regulation is associated with histone acetylation, DNA demethylation, and activation of the exon 17 GR promoter [16]. The relevance of these effects in humans has recently been demonstrated by Oberlander et al. [17] in the analysis of methylation status of the GR promotor at NGFI-A binding sites in cord blood mononuclear cells of infants exposed to third trimester maternal depressed or anxious mood. Maternal depression was found to be associated with increased GR 1F promotor methylation in fetal blood samples and these methylation patterns predicted HPA reactivity in infants at 3 months of age [17]. Analysis of hippocampal tissue from suicide victims with a history of childhood abuse similarly indicates lower GR expression and higher GR 1F promotor methylation associated with disruptions of the early environment and confirms the findings from rodent studies that differential NGFI-A binding is a functional consequence of these epigenetic effects [18]. However, the impact of perinatal mother� infant interactions is not limited to GR regulation as illustrated by Roth et al. [19] examining the effects of postnatal abuse on offspring brain derived neurotrophic factor (BDNF) methylation [19]. In rats, an increase in methylation of exon IV of the BDNF promotor and consequent decrease in BDNF mRNA in the prefrontal cortex was found in association with exposure to periods of abusive maternal care (dragging, rough handling, etc.). As was the case with the effects of individual differences in maternal care, these effects emerged in infancy and were sustained into adulthood. Moreover, these effects on BDNF exon IV methylation are perpetuated to the F1 generation suggesting a role for epigenetic mechanisms in transgenerational effects [20].

Development Across The Lifespan: Epigenetics & Experience Dependent Plasticity

The previous section highlights the stable effects of early life experiences and how these events become encoded at a molecular level. Another approach to the study of epigenetics and development comes from studies of synaptic plasticity during the expression of long-term potentiation (LTP) and memory consolidation. High levels of maternal care and exposure to juvenile environ- mental enrichment (EE) have been demonstrated to improve capacity for learning and memory associated with LTP enhancement [21,22]. Moreover, recent evidence suggests that EE modulates NMDAr/p38/LTP signaling pathways in the hippocampus and improves contextual fear memory formation across generations such that offspring of enriched mothers likewise show enhanced LTP even when cross-fostered at birth to non- enriched mothers [23]. Environmental enrichment has been associated with increased histone acetylation in the hippocampus and improved spatial memory [24,25]. Pharmacological targeting of the epigenome has been used to demonstrate the role of histone acetylation and DNA methylation in the consolidation of long-term memory [26]. Treatment with zebularine (an inhibitor or DNA methyltransferases) has been shown to block memory formation and reduce histone acetylation following con- textual fear conditioning in adult rats [27] whereas treatment with the HDAC inhibitor sodium butyrate lead to enhanced formation of contextual fear memories [28]. The particular HDAC target of these inhibitors may be HDAC2 as recent evidence has emerged illustrating decreased synaptic plasticity and memory formation in mice over-expressing HDAC2 but not HDAC1; with the converse effect in HDAC2-deficient mice [29]. These studies illustrate a possible relationship between synaptic activity and histone acetylation/DNA methylation in mature neurons, suggesting that there is continued plasticity in these epigenetic systems beyond the prenatal and postnatal periods of development.

Epigenetic Mechanism & The Regulation Of Synaptic Transmission

Activity-dependent changes in gene expression within neuronal pathways during development may serve as a critical pathway linking experience of the external environment and epigenetic modifications within the cell nucleus. In a recent study, Monteggia and colleagues elegantly demonstrated that spontaneous synaptic trans- mission in hippocampal neurons is regulated by alterations in DNA methylation that occur in response to synaptic activity [30]. Treatment with a DNMT inhibitor lead to a significant decrease in frequency of miniature excitatory post-synaptic currents (mEPSCs) and rate of spontaneous synaptic vesicle fusion correlated with a decrease in BDNF promoter I methylation and increased BDNF expression. This effect was blocked with inhibition of synaptic activity and reductions in mEPSCs were prevented in the absence of MeCP2. These results strongly suggest a role for DNA methylation/MeCP2 pathways in the control of synaptic function. Activity- dependent phosphorylation of MeCP2 via Ca2+-calmodulindependent kinase II has been shown to cause MeCP2 dissociation from target genes and relieve transcriptional repression [31]. Consequently, genes such as BDNF are increased in expression leading to normal dendritic patterning and dendritic spine development [32]. These findings suggest an epigenetic mechanism through which neurons can monitor alterations in activity level and adjust neurotransmitter output via altered gene expression with consequences for network excitability and circuit refinement. Impairments in these MeCP2 pathways may lead to several neurodevelopmental abnormalities including Rett syndrome, infantile autism, mental retardation, and schizophrenia [33] and targeted deletion of MeCP2 in the amygdala has recently been demonstrated to impair learning and memory and lead to increased anxiety-like behavior in mice [34].

Epigenetic Control Of Critical Period Plasticity

Though epigenetic mechanisms have certainly been implicated in mediating the high levels of plasticity in early development, it is also possible to view the decreased plasticity and sensitivity that occurs later in development from an epigenetic perspective. Neocortical circuits are extremely sensitive to manipulations of the sensory environment during restricted temporal windows of postnatal development called �critical periods�. For example, an imbalance in binocular vision during child- hood affects perception leading to amblyopia or �lazy eye�. Monocular deprivation (MD) reproduces this classical paradigm of experience-dependent plasticity [35]. The striking physiological effect of MD is a shift in visual cortical neuron response in favor of the non-deprived eye; an example of ocular dominance (OD) plasticity. The critical period during which this OD plasticity occurs is defined by the activation and subsequent inhibition of specific molecular pathways involving signaling molecules such as aCaMKII, calcineurin, PKA, ERK, and CREB [36]. Recently, Pizzorusso and colleagues identified rapid increases in ERK-dependent phosphorylation of histones associated with activation of the juvenile visual cortex and a developmental downregulation of this effect in older mice [37]. In adult mice, the reduced OD plasticity can be reinstated through treatment with the HDAC inhibitor trichostatin A (TSA). Multiple cellular mechanisms might contribute to experience-dependent plasticity expression [38]. Further work is necessary to understand if epigenetic mechanisms are generally acting in all cellular substrates or only within a specific subset.

Myelin maturation has also been proposed as one of the major factors contributing to decreased neuronal plasticity. During the onset of critical period plasticity, oligodendrocytes start to express specific myelin structural proteins, including myelin basic protein (MBP), myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (OMgp) and myelin-associated oligodendrocyte basic protein (MOBP) [39]. As myelination reaches adult levels, OD plasticity is strongly reduced or absent. MAG and OMgp may contribute to critical period closure through activation of Nogo receptors. Indeed, mice lacking Nogo receptors exhibit OD plasticity even in adulthood [40]. Manipulation of epigenetic status of oligodendrocytes may also be an effective strategy for modulating plasticity. Casaccia-Bonnefil and colleagues have shown that histone modifications are involved in oligodendrocyte precursor cell (OPC) differentiation during development and in recovery from injury [41� 43]. Administration of the HDAC inhibitor valproic acid during the critical period of myelination onset was found to prevent the OPC maturation into myelinating cells. These results suggest that HDAC activity during a specific temporal window of postnatal development is required for OPC differentiation and myelination. At later developmental stages, histone deacetylation subsides and is replaced by repressive histone methylation and the establishment of a compact chromatin structure, characteristic of the differentiated oligodendrocyte phenotype [43]. Shen et al. [44] found that in response to damage of oligodendrocytes, robust remyelination occurred in juvenile but not in older animals with the new myelin synthesis preceded by down regulation of oligodendrocyte differentiation inhibitors and neural stem cell markers and the recruitment of HDACs to promoter regions. This HDAC recruitment is inefficient in older brains, allowing for the accumulation of transcriptional inhibitors and prevention of myelin gene expression. This age-depend- ent effect can be induced in young mice treated with HDAC inhibitors during the period when damage to oligodentrocytes is occurring. Thus, there are epigenetic changes that are characteristic of periods of developmental plasticity that could provide a target for therapeutic intervention in the event of CNS damage. The use of HDAC inhibitors to increase plasticity in the brain may be a promising therapeutic approach as there is conver- ging evidence from rodent models that treatment with these compounds (1) can lead to dramatic shifts in gene expression and behavior in adult offspring who have received low levels of maternal care [15] and (2) mimic the effects of EE on reversal of neurodevelopmental abnormalities [24]. Rather than producing a generalized increase in transcription, these compounds lead to acti- vation of a specific subset of genes [45�47], suggesting possible targeted intervention to reinstate plasticity in adult brain.

Conclusions

There is converging evidence for the role of epigenetic modifications such as histone acetylation and DNA meth- ylation in both the stability and plasticity of developing neuronal circuits. The persistent effects on gene expression that can be achieved through these mechanisms provide a biological route through which environmental experiences can become embedded, leading to long-term changes in neurobiology and behavior. Enhancing plasticity in the adult brain is an exciting prospect and there is certainly evidence emerging that suggest the possible use of epigenetic factors to induce a �younger� brain. The challenge of future studies is to establish the pathways through which site-specific and gene-specific transcriptional modifications can be achieved and to better understand the route through which experiences across the lifespan induce this molecular plasticity.

Michela Fagiolini 1, Catherine L Jensen 2 and Frances A Champagne 2

Current Opinion in Neurobiology 2009, 19:1�6
This review comes from a themed issue on Development
Edited by Takao Hensch and Andrea Brand
0959-4388/$ � see front matter Published by Elsevier Ltd.
DOI 10.1016/j.conb.2009.05.009

Corresponding author: Champagne, Frances A (fac2105@columbia.edu)

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Close Accordion:

Epigenetic Influences On Brain Development And Plasticity

Epigenetic Influences On Brain Development And Plasticity

Epigenetic: A fine interplay exists between sensory experience and innate genetic programs leading to the sculpting of neuronal circuits during early brain development. Recent evidence suggests that the dynamic regulation of gene expression through epigenetic mechanisms is at the interface between environmental stimuli and long lasting molecular, cellular and complex behavioral phenotypes acquired during periods of developmental plasticity. Understanding these mechanisms may give insight into the formation of critical periods and provide new strategies for increasing plasticity and adaptive change in adulthood.

Introduction

During early development, neuronal circuits are created and connections between neurons undergo remodeling as they develop their adult functional properties in response to the surrounding environment. The adult brain loses this extraordinary plasticity. Recent findings support a key role of epigenetic factors in mediating the effects of sensory experience on site-specific gene expression, synaptic transmission, and behavioral phenotypes. Here we review recent evidence implicating multiple epigenetic mechanisms in experience-dependent changes during development and discuss their role in critical period expression in the developing and adult brain.

Epigenetics: Molecular Mechanisms Of Gene Regulation

The term �epigenetic� refers to chromatin modifications which alter gene expression without affecting DNA sequence. The factors that contribute to the epigenetic regulation of transcriptional activity are numerous and include microRNA [1], DNA methylation [2,3] and post- translational modifications of nucleosomal histones [2,4]. DNA methylation refers to a chemical modification to DNA whereby cytosine is converted to 5-methylcytosine with the consequence of reduced accessibility of the DNA to transcription factors (Figure 1a�d). These modi- fications can be stable and heritable and provide a critical mechanism in cellular differentiation [3]. The process of methylation is dependent on the presence of methyl donors (provided by nutrients such as folic acid, meth- ionine and choline) and methyltransferases which med- iate either maintenance (i.e. DNMT1) or de novo DNA methylation (i.e. DNMT3). Transcriptional repression associated with DNA methylation is further sustained through methyl-binding proteins such as MeCP2 [5]. Epigenetic control of gene expression is also mediated through multiple post-translational modifications of histone proteins, including methylation, acetylation and ubiquination, which can alter the accessibility of DNA and the density of chromatin structure (Figure 1e,f). In particular, histone acetylation is associated with increased transcriptional activity whereas histone deacetylation is associated with transcriptional repression. The acetylation state of these nucleosomal proteins is controlled by the presence of histone acetyltransferases (HATs), histone deacetylases (HDACs), which are recruited by methyl-binding proteins, and by HDAC inhibitors, which effectively increase gene expression through shifting histones to an acetylated state [2,6]. The timing and degree of gene expression are controlled through these complex mechanisms, thus providing a link between single genotypes and multiple phenotypes.

Epigenetic Factors & The Influence Of Early Life Experiences

In mammalian development, the prenatal and postnatal periods are characterized by rapid changes in neuronal organization, thus providing a critical window of opportunity during which environmental experiences can lead to long-term influences on brain and behavior. There is increasing evidence for the role of epigenetic factors in mediating the relationship between these experiences and long-term outcomes. Mueller and Bale [7] have recently demonstrated decreased DNA methylation of the corticotrophin-releasing-factor (CRF) gene promotor and increased methylation of the glucocorticoid receptor (GR) exon 17 promotor region in hypothalamic tissue of adult male mice born to gestationally stressed females. These epigenetic modifications are associated with exposure to stress during the early stages of prenatal development and may involve dysregulation of placental gene expression. The nutritional environment during fetal development has likewise been demonstrated to influence growth, metabolism and brain development and there is increasing evidence that dietary levels of methyl-donors can epigenetically alter gene expression in offspring [8,9]. In rats, Lillycrop et al. [10] illustrate that GR 110 and PPARa (peroxisome proliferator-activated receptor alpha) gene promotor methylation is reduced in the hepatic tissue of offspring born to protein restricted dams whereas methylation is increased in offspring of dams whose diet is supplemented with methyl donors [10,11]. These effects may be related to DNMT1 expression, which is likewise decreased with dietary protein restriction [11]. Prenatal nutritional regulation of DNA methylation has similarly been observed in brain tissue associated with levels of DNMT1 expression [12], suggesting that in the rapid period of cell division ocurring during fetal development, the level of methyl donors can have a significant impact on transcriptional activity that is maintained into adulthood.

epigenetic el paso tx.The role of epigenetic modification in sustaining the effects of environmental experience has also been demonstrated in the context of postnatal mother�infant interactions. Individual variations in maternal care during the immediate postpartum period in rats are associated with changes in offspring hypothalamic-pituitary-adrenal (HPA) activity, neuroendocrine systems involved in reproduction and hippocampal plasticity [13]. Analyses of levels of promotor methylation within the hippocampal GR 17 and hypothalamic ERa genes in offspring of rat dams that provide high vs. low levels of maternal care indicate that high levels of care are associated with decreased promotor methylation and thus increased gene expression [14,15]. Though the route through which these epigenetic changes are mediated is not yet clear, there is evidence for increased binding of nerve growth factor-inducible protein A (NGFI-A) to the GR exon 17 promoter amongst offspring who receive high levels of care in infancy [15] and in vitro models suggest that NGFI-A up-regulation is associated with histone acetylation, DNA demethylation, and activation of the exon 17 GR promoter [16]. The relevance of these effects in humans has recently been demonstrated by Oberlander et al. [17] in the analysis of methylation status of the GR promotor at NGFI-A binding sites in cord blood mononuclear cells of infants exposed to third trimester maternal depressed or anxious mood. Maternal depression was found to be associated with increased GR 1F promotor methylation in fetal blood samples and these methylation patterns predicted HPA reactivity in infants at 3 months of age [17]. Analysis of hippocampal tissue from suicide victims with a history of childhood abuse similarly indicates lower GR expression and higher GR 1F promotor methylation associated with disruptions of the early environment and confirms the findings from rodent studies that differential NGFI-A binding is a functional consequence of these epigenetic effects [18]. However, the impact of perinatal mother� infant interactions is not limited to GR regulation as illustrated by Roth et al. [19] examining the effects of postnatal abuse on offspring brain derived neurotrophic factor (BDNF) methylation [19]. In rats, an increase in methylation of exon IV of the BDNF promotor and consequent decrease in BDNF mRNA in the prefrontal cortex was found in association with exposure to periods of abusive maternal care (dragging, rough handling, etc.). As was the case with the effects of individual differences in maternal care, these effects emerged in infancy and were sustained into adulthood. Moreover, these effects on BDNF exon IV methylation are perpetuated to the F1 generation suggesting a role for epigenetic mechanisms in transgenerational effects [20].

Development Across The Lifespan: Epigenetics & Experience Dependent Plasticity

The previous section highlights the stable effects of early life experiences and how these events become encoded at a molecular level. Another approach to the study of epigenetics and development comes from studies of synaptic plasticity during the expression of long-term potentiation (LTP) and memory consolidation. High levels of maternal care and exposure to juvenile environ- mental enrichment (EE) have been demonstrated to improve capacity for learning and memory associated with LTP enhancement [21,22]. Moreover, recent evidence suggests that EE modulates NMDAr/p38/LTP signaling pathways in the hippocampus and improves contextual fear memory formation across generations such that offspring of enriched mothers likewise show enhanced LTP even when cross-fostered at birth to non- enriched mothers [23]. Environmental enrichment has been associated with increased histone acetylation in the hippocampus and improved spatial memory [24,25]. Pharmacological targeting of the epigenome has been used to demonstrate the role of histone acetylation and DNA methylation in the consolidation of long-term memory [26]. Treatment with zebularine (an inhibitor or DNA methyltransferases) has been shown to block memory formation and reduce histone acetylation following con- textual fear conditioning in adult rats [27] whereas treatment with the HDAC inhibitor sodium butyrate lead to enhanced formation of contextual fear memories [28]. The particular HDAC target of these inhibitors may be HDAC2 as recent evidence has emerged illustrating decreased synaptic plasticity and memory formation in mice over-expressing HDAC2 but not HDAC1; with the converse effect in HDAC2-deficient mice [29]. These studies illustrate a possible relationship between synaptic activity and histone acetylation/DNA methylation in mature neurons, suggesting that there is continued plasticity in these epigenetic systems beyond the prenatal and postnatal periods of development.

Epigenetic Mechanism & The Regulation Of Synaptic Transmission

Activity-dependent changes in gene expression within neuronal pathways during development may serve as a critical pathway linking experience of the external environment and epigenetic modifications within the cell nucleus. In a recent study, Monteggia and colleagues elegantly demonstrated that spontaneous synaptic trans- mission in hippocampal neurons is regulated by alterations in DNA methylation that occur in response to synaptic activity [30]. Treatment with a DNMT inhibitor lead to a significant decrease in frequency of miniature excitatory post-synaptic currents (mEPSCs) and rate of spontaneous synaptic vesicle fusion correlated with a decrease in BDNF promoter I methylation and increased BDNF expression. This effect was blocked with inhibition of synaptic activity and reductions in mEPSCs were prevented in the absence of MeCP2. These results strongly suggest a role for DNA methylation/MeCP2 pathways in the control of synaptic function. Activity- dependent phosphorylation of MeCP2 via Ca2+-calmodulindependent kinase II has been shown to cause MeCP2 dissociation from target genes and relieve transcriptional repression [31]. Consequently, genes such as BDNF are increased in expression leading to normal dendritic patterning and dendritic spine development [32]. These findings suggest an epigenetic mechanism through which neurons can monitor alterations in activity level and adjust neurotransmitter output via altered gene expression with consequences for network excitability and circuit refinement. Impairments in these MeCP2 pathways may lead to several neurodevelopmental abnormalities including Rett syndrome, infantile autism, mental retardation, and schizophrenia [33] and targeted deletion of MeCP2 in the amygdala has recently been demonstrated to impair learning and memory and lead to increased anxiety-like behavior in mice [34].

Epigenetic Control Of Critical Period Plasticity

Though epigenetic mechanisms have certainly been implicated in mediating the high levels of plasticity in early development, it is also possible to view the decreased plasticity and sensitivity that occurs later in development from an epigenetic perspective. Neocortical circuits are extremely sensitive to manipulations of the sensory environment during restricted temporal windows of postnatal development called �critical periods�. For example, an imbalance in binocular vision during child- hood affects perception leading to amblyopia or �lazy eye�. Monocular deprivation (MD) reproduces this classical paradigm of experience-dependent plasticity [35]. The striking physiological effect of MD is a shift in visual cortical neuron response in favor of the non-deprived eye; an example of ocular dominance (OD) plasticity. The critical period during which this OD plasticity occurs is defined by the activation and subsequent inhibition of specific molecular pathways involving signaling molecules such as aCaMKII, calcineurin, PKA, ERK, and CREB [36]. Recently, Pizzorusso and colleagues identified rapid increases in ERK-dependent phosphorylation of histones associated with activation of the juvenile visual cortex and a developmental downregulation of this effect in older mice [37]. In adult mice, the reduced OD plasticity can be reinstated through treatment with the HDAC inhibitor trichostatin A (TSA). Multiple cellular mechanisms might contribute to experience-dependent plasticity expression [38]. Further work is necessary to understand if epigenetic mechanisms are generally acting in all cellular substrates or only within a specific subset.

Myelin maturation has also been proposed as one of the major factors contributing to decreased neuronal plasticity. During the onset of critical period plasticity, oligodendrocytes start to express specific myelin structural proteins, including myelin basic protein (MBP), myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (OMgp) and myelin-associated oligodendrocyte basic protein (MOBP) [39]. As myelination reaches adult levels, OD plasticity is strongly reduced or absent. MAG and OMgp may contribute to critical period closure through activation of Nogo receptors. Indeed, mice lacking Nogo receptors exhibit OD plasticity even in adulthood [40]. Manipulation of epigenetic status of oligodendrocytes may also be an effective strategy for modulating plasticity. Casaccia-Bonnefil and colleagues have shown that histone modifications are involved in oligodendrocyte precursor cell (OPC) differentiation during development and in recovery from injury [41� 43]. Administration of the HDAC inhibitor valproic acid during the critical period of myelination onset was found to prevent the OPC maturation into myelinating cells. These results suggest that HDAC activity during a specific temporal window of postnatal development is required for OPC differentiation and myelination. At later developmental stages, histone deacetylation subsides and is replaced by repressive histone methylation and the establishment of a compact chromatin structure, characteristic of the differentiated oligodendrocyte phenotype [43]. Shen et al. [44] found that in response to damage of oligodendrocytes, robust remyelination occurred in juvenile but not in older animals with the new myelin synthesis preceded by down regulation of oligodendrocyte differentiation inhibitors and neural stem cell markers and the recruitment of HDACs to promoter regions. This HDAC recruitment is inefficient in older brains, allowing for the accumulation of transcriptional inhibitors and prevention of myelin gene expression. This age-depend- ent effect can be induced in young mice treated with HDAC inhibitors during the period when damage to oligodentrocytes is occurring. Thus, there are epigenetic changes that are characteristic of periods of developmental plasticity that could provide a target for therapeutic intervention in the event of CNS damage. The use of HDAC inhibitors to increase plasticity in the brain may be a promising therapeutic approach as there is conver- ging evidence from rodent models that treatment with these compounds (1) can lead to dramatic shifts in gene expression and behavior in adult offspring who have received low levels of maternal care [15] and (2) mimic the effects of EE on reversal of neurodevelopmental abnormalities [24]. Rather than producing a generalized increase in transcription, these compounds lead to acti- vation of a specific subset of genes [45�47], suggesting possible targeted intervention to reinstate plasticity in adult brain.

Conclusions

There is converging evidence for the role of epigenetic modifications such as histone acetylation and DNA meth- ylation in both the stability and plasticity of developing neuronal circuits. The persistent effects on gene expression that can be achieved through these mechanisms provide a biological route through which environmental experiences can become embedded, leading to long-term changes in neurobiology and behavior. Enhancing plasticity in the adult brain is an exciting prospect and there is certainly evidence emerging that suggest the possible use of epigenetic factors to induce a �younger� brain. The challenge of future studies is to establish the pathways through which site-specific and gene-specific transcriptional modifications can be achieved and to better understand the route through which experiences across the lifespan induce this molecular plasticity.

Michela Fagiolini 1, Catherine L Jensen 2 and Frances A Champagne 2

Current Opinion in Neurobiology 2009, 19:1�6
This review comes from a themed issue on Development
Edited by Takao Hensch and Andrea Brand
0959-4388/$ � see front matter Published by Elsevier Ltd.
DOI 10.1016/j.conb.2009.05.009

Corresponding author: Champagne, Frances A (fac2105@columbia.edu)

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Rodent study showing that environmental enrichment increases histone
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26. Sweatt JD: Experience-dependent epigenetic modifications in
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27. Lubin FD, Roth TL, Sweatt JD: Epigenetic regulation of BDNF
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Recent paper from a series of investigations by the Sweatt lab illustrating
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28. Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P,
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29. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N,
Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R et al.: HDAC2
negatively regulates memory formation and synaptic
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Study in mice examining the particular HDAC target through which HDAC
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targeted up- and downregulation of HDAC2 the authors illustrate the
importance of levels of this enzyme in mediating cognitive enhancement

30. Nelson ED, Kavalali ET, Monteggia LM: Activity-dependent
suppression of miniature neurotransmission through the
regulation of DNA methylation. J Neurosci 2008, 28:395-406.

This paper focuses on the regulation of DNA methylation by NMDA
receptor-mediated synaptic activity within mature neurons and how
epigenetic alterations affect basal synaptic function. These findings
suggest a synaptic basis for neurological symptoms associated with
neurodevelopmental disorders such as Rett syndrome

31. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC,
Jaenisch R, Greenberg ME: Derepression of BDNF transcription
involves calcium-dependent phosphorylation of MeCP2.
Science 2003, 302:885-889.

32. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L,
Chen WG, Lin Y, Savner E, Griffith EC et al.: Brain-specific
phosphorylation of MeCP2 regulates activity-dependent Bdnf
transcription, dendritic growth, and spine maturation. Neuron
2006, 52:255-269.

33. Moretti P, Zoghbi HY: MeCP2 dysfunction in Rett syndrome and
related disorders. Curr Opin Genet Dev 2006, 16:276-281.

34. Adachi M, Autry AE, Covington HE 3rd, Monteggia LM: MeCP2-
mediated transcription repression in the basolateral amygdala
may underlie heightened anxiety in a mouse model of Rett
syndrome. J Neurosci 2009, 29:4218-4227.

35. Tropea D, Van Wart A, Sur M: Molecular mechanisms of
experience-dependent plasticity in visual cortex. Philos Trans
R Soc Lond B Biol Sci 2009, 364:341-355.

36. Medini P, Pizzorusso T: Visual experience and plasticity of the
visual cortex: a role for epigenetic mechanisms. Front Biosci
2008, 13:3000-3007.

37. Putignano E, Lonetti G, Cancedda L, Ratto G, Costa M, Maffei L,
Pizzorusso T: Developmental downregulation of histone
posttranslational modifications regulates visual cortical
plasticity. Neuron 2007, 53:747-759.

The authors identify ERK/MAPK-dependent regulation of histone modifications
as a new mechanism underlying the expression of ocular
dominance plasticity

38. Hensch TK: Critical period mechanisms in developing visual
cortex. Curr Top Dev Biol 2005, 69:215-237.

39. Quarles RH: Myelin sheaths: glycoproteins involved in their
formation, maintenance and degeneration. Cell Mol Life Sci
2002, 59:1851-1871.

40. McGee AW, Yang Y, Fischer QS, Daw NW, Strittmatter SM:
Experience-driven plasticity of visual cortex limited by myelin
and Nogo receptor. Science 2005, 309:2222-2226.

41. He Y, Dupree J, Wang J, Sandoval J, Li J, Liu H, Shi Y, Nave KA,
Casaccia-Bonnefil P: The transcription factor Yin Yang 1 is
essential for oligodendrocyte progenitor differentiation.
Neuron 2007, 55:217-230.

42. Shen S, Casaccia-Bonnefil P: Post-translational modifications
of nucleosomal histones in oligodendrocyte lineage
cells in development and disease. J Mol Neurosci 2008,
35:13-22.

43. Shen S, Li J, Casaccia-Bonnefil P: Histone modifications
affect timing of oligodendrocyte progenitor differentiation
in the developing rat brain. J Cell Biol 2005, 169:
577-589.

44. Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJ,
Casaccia-Bonnefil P: Age-dependent epigenetic control of
differentiation inhibitors is critical for remyelination efficiency.
Nat Neurosci 2008, 11:1024-1034.

This paper provides mechanistic insight into how oligodendrocytes precursors
cell differentiation is epigenetically regulated during remyelination
and how these mechanisms change with aging.

45. Fass DM, Butler JE, Goodman RH: Deacetylase activity is
required for cAMP activation of a subset of CREB target
genes. J Biol Chem 2003, 278:43014-43019.

46. Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA,
Cabrera SM, McDonough CB, Brindle PK, Abel T et al.: Histone
deacetylase inhibitors enhance memory and synaptic
plasticity via CREB:CBP-dependent transcriptional activation.
J Neurosci 2007, 27:6128-6140.

47. Weaver IC, Meaney MJ, Szyf M: Maternal care effects on the
hippocampal transcriptome and anxiety-mediated behaviors
in the offspring that are reversible in adulthood. Proc Natl Acad
Sci U S A 2006, 103:3480-3485.
[/accordion]
[/accordions]

Introduction To The Cerebellum | El Paso, TX. | Part II

Introduction To The Cerebellum | El Paso, TX. | Part II

El Paso, TX. Chiropractor, Dr. Alexander Jimenez continues with the cerebellum overview. The cerebellum is one of the most identifiable parts of the brain based on its unique shape and location. It is an extremely important part of the brain. It is responsible for being able to perform everyday voluntary tasks likes walking and writing. And it’s essential for being able to keep balance and remain upright. People who have suffered from a damaged cerebellum struggle with balance and maintaining proper muscle coordination.

EVERYTHING PERIPHERAL HAS A CENTRAL CONSEQUENCE!

CASE STUDY

Cerebellar Ataxia

54-YEAR-OLD FEMALE PRESENTED TO OUR CLINIC FOR FEELINGS OF �UNSTEADINESS�

cerebellum el paso tx.

  • Patient woke up one morning over one year ago with vertigo.cerebellum el paso tx.
  • Patient has difficulty with balance and walking. She sometimes resorts to using a cane. Extreme difficulty walking downstairs
  • Patient has been proactive in her weight loss, however, this has served as a speed bump in her plan of getting back to health.
  • She has not been able to exercise like she had in the past.
  • Patient has been to several vestibular rehabilitation clinics to no avail.

 

 

 

 

 

PHYSICAL EXAMINATION HIGHLIGHTS

  • cerebellum el paso tx.Cranial nerves I-XII WNL
  • Wide-based gait
  • Right cerebellar findings
  • Provocative Romberg testing produced significant sway in the right posterior and left anterior canal position.

 

 

 

 

 

 

 

 

THERAPEUTIC INTERVENTIONS

 

 

 

 

 

 

 

 

AFTER 1ST DAY

  • cerebellum el paso tx.Marked improvement in balance.
  • Comfortable walking and standing with more narrow- based gait.
  • Ability to walk down stairs without holding handrail.

 

 

 

 

CASE STUDY

Meet Aaron & McKayla

cerebellum el paso tx.

**Permission given to use names, images and whatever else needed to spread the word

A 39-year-old retired Explosives Ordinance Disposal Technician who in 2011…

cerebellum el paso tx.

And in 2015…

cerebellum el paso tx.

WHAT CAN FUNCTIONAL NEUROLOGY DO FOR AARON?

HOW CAN WE HELP HIS BALANCE?

 

IF YOU DON�T USE IT….

cerebellum el paso tx.WHAT DO YOU SEE?

cerebellum el paso tx.WHAT DO YOU SEE?

cerebellum el paso tx.

WHAT DO YOU SEE?

cerebellum el paso tx.

WHAT DO YOU SEE?

WHAT DOES IT MEAN?

cerebellum el paso tx.

cerebellum el paso tx.AFFERENTATION WITH METABOLIC CONSIDERATIONS

A-BETA – MECHANORECEPTORS
  • Merkel�s disc � slow adapting to pressure and texture. Sharpest resolution for spatial patterning. �steady light pressure�
  • Meissner�s Corupuscle � superfiicial motion detection. Two point discretion.
  • Ruffini�s Corpuscle � located in dermis. Steady skin stretch and joint pressure.
  • Pacinian Corpuscle � rapid adapter, Associated with vibration.
GOLGI TENDON ORGAN IB FIBERS
  • Responds to muscle tension changes.

cerebellum el paso tx.

1A IIA SOMATOSENSORY
  • Muscle spindle fiber is the largest fiber in the human body.
  • Respond to the rate of change in muscle length, as well to change in velocity, rapidly adapting.
  • This will require the most demands on metabolic capacity.

BACK TO THE CASE

  • cerebellum el paso tx.In 2011, Aaron had lost both of his eyes in an IED explosion.
  • Due to the blast, Aaron also lost his sense of smell and taste.
  • After several months of rehab, Aaron learned how to �be really good at being blind.�
  • Although he could not see, balance was no major issue. �I was climbing mountains, running marathons, kayaking…you name it.�

 

 

 

 

 

  • In 2015, a few months after running the Boston Marathon, Aaron was on the phone with Mckayla.
  • �He said he was not feeling well and was going to go lie down. I was concerned but did not think much of it.�
  • After a day and a half of waiting for his call, McKayla found out Aaron contracted meningitis and was intubated in the ICU.

cerebellum el paso tx.

  • Finding out Aaron is completely deaf after meningitis…

cerebellum el paso tx.

  • The meningitis obliterated his hearing and left him completely deaf for 5 months.
  • Not only that, the meningitis wreaked havoc on Aaron�s balance centers (his vestibulocerebellum) and he suffered from severe vertigo and difficulty standing and walking.
cerebellum el paso tx.After recovering from meningitis:
  • �You can see how he’s walking on the treadmill in the very beginning. It took so much out of him to be able to do that.� � Mckayla
  • Remember �metabolic capacity?�

cerebellum el paso tx.

  • Aaron was actually able to get himself back into running shape and ran one of his best times in Ohio, but not without struggle.
  • �Every little change in pace and every little movement was a huge calibration for me and it took a lot out of me.�
  • �I still have a lot of work to do…�

cerebellum el paso tx.

cerebellum el paso tx.CHALLENGE ACCEPTED

  • Sooooo….back to the basics!

cerebellum el paso tx.

  • We utilized different surfaces to challenge his balance system (foam pads, wobble boards, etc….
  • We also had him do most of his therapies barefoot to increase afferentation to the somatosensory cortex

cerebellum el paso tx.Updates from McKayla:

  • �Pace is a 7:30 and he’s doing 6 miles. Completed core work too.�

cerebellum el paso tx.

  • Typically in the OVARD we would spin Aaron in specific directions and he would tell us which direction he was spinning in.
  • At first this was very difficult and he could not perceive the movement, however it was not long until he was sensing each direction of his spin.
  • We let him have a little fun in this particular video….

cerebellum el paso tx.

  • I asked Aaron and McKayla how they felt therapy was going.
  • They responded �great, but we won�t really know until he goes for a run outside…�
  • So we went on a seven mile run at an 8 minute pace.
  • Here we are working on turns.

cerebellum el paso tx.

  • Cured!
  • Aaron is back home in Florida continuing his training for Boston in two weeks.
  • He is continuing at-home exercises and vestibular rehab with specialists
  • He and I are running a half marathon together in the not-so-distant future

cerebellum el paso tx.SOME SIMPLE CEREBELLAR THERAPIES

GENERAL CEREBELLAR EXERCISES

  • Spinning in desk chair will stimulate ipsilateral cerebellum
  • Passive muscle stretch will stimulate ipsilateral cerebellum
  • Squeezing tennis ball will stimulate ipsilateral cerebellum
  • Passive or active non-linear complex movements will stimulate ipsilateral cerebellum
  • Finger to nose pointing will stimulate ipsilateral cerebellum

Vermal & Paravermal Exercises

  • Passive and active gaze stabilization exercises with central fixation
  • Wobble board/unsteady surface exercises
  • Balance beam exercises and tandem walking
  • Bouncing a ball against the ground or throwing it against the wall
  • Core exercises such as planks, sit-ups and yoga
  • Learning how to balance on a bicycle
  • Supine cross crawl activity

Lateral Cerebellum Exercises

  • Cognitive processes
  • Learning a musical instrument
  • Tracing a maze
  • Playing �catch�
  • Tapping fingers/hand or toes/feet to the beat of a metronome
  • Trying to write with eyes closed
  • Strategic board games

THE LANGUAGE OF THE BRAIN IS REPETITION!

By RYAN CEDERMARK, RN BSN MSN DC DACNB

Introduction To The Cerebellum | El Paso, TX. | Part I

Introduction To The Cerebellum | El Paso, TX. | Part I

El Paso, TX. Chiropractor Dr. Alexander Jimenez presents an introduction to the cerebellum. The brain is a complex structure that has billions of nerve cells. The basic anatomy is easily understandable. But there is one part of the brain, the cerebellum, which is involved in virtually all movement. This is the part of the brain that helps a person drive, throw a ball, or walk across the street.

Problems with the cerebellum are uncommon and mostly involve movement and coordination difficulties. This article will give an overview of the anatomy, purpose, and disorders of the cerebellum, as well as, how to keep the brain healthy.

FAGIOLINI ET AL. EPIGENETIC INFLUENCES ON BRAIN DEVELOPMENT AND PLASTICITY CURR OPIN NEUROBIOL, 2009

cerebellum el paso tx.

  • �Enhancing plasticity in the adult brain is an exciting prospect and there is certainly evidence emerging that suggest the possible use of epigenetic factors to induce a �younger� brain.�
  • �Recent findings support a key role of epigenetic factors in mediating the effects of sensory experience on site-specific gene expression, synaptic transmission, and behavioral phenotypes.�

 

 

 

 

 

TAYLOR ET AL. CUTTING YOUR NERVE CHANGES YOUR BRAIN BRAIN, 2009

  • �Animal studies have established that plasticity within the somatosensory cortex begins immediately following peripheral nerve transection, and that 1 year after complete nerve transection and surgical repair, cortical maps contain patchy, noncontinuous representations of the transected and adjacent nerves.�
  • �Here, we have demonstrated for the first time that there is functional plasticity and both grey and white matter structural abnormalities in several cortical areas following upper limb peripheral nerve transection and surgical repair.�

cerebellum el paso tx.

THE CEREBELLUM

cerebellum el paso tx.

cerebellum el paso tx.

cerebellum el paso tx.

IMPORTANT FUNCTIONAL AREAS OF THE CEREBELLUM

  • Spinocerebellum
  • Vestibulocerebellum
  • Cerebrocerebellum

cerebellum el paso tx.

SPINOCEREBELLUM

  • cerebellum el paso tx.Responsibilities:

  • Regulation of muscle tone for posture and locomotion
  • Balance
  • Patient Complaints:

  • Difficulty with balance
  • Difficulty walking in the dark
  • Difficulty going down stairs
  • Sway to one side while walking
  • Examination Findings:

  • Wide based gait
  • Sway in Romberg�s position

 

 

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

WHAT DO YOU SEE?

cerebellum el paso tx.

cerebellum el paso tx.WHAT CAN YOU DO?

  • cerebellum el paso tx.Have the patient perform balance exercises:

  • Practice Romberg�s
  • Practice one leg standing
  • Bosu Ball exercises
  • Foam Pad exerscises
  • Balance Board exercises
  • Increase core stability:

  • Plank�s
  • Yoga
  • Increase proprioception:

  • Adjust!
  • But which side?

VESTIBULOCEREBELLUM

  • cerebellum el paso tx.

    Responsibilities:

  • Regulation of vestibular system
  • Regulation of balance
  • Assistance with eye movements (encoding retinal slip)
  • Patient Complaints:

  • Postural muscle fatigue
  • Dizziness
  • Disorientation
  • Difficulty riding in a car
  • Nausea
  • Examination Findings:

  • Wide based gait
    Sway in Romberg�s position
  • Nystagmus
  • Impaired VOR
  • Impaired smooth pursuits
  • Hypermetric Saccades

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

cerebellum el paso tx.

cerebellum el paso tx.

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

VOR

cerebellum el paso tx.

cerebellum el paso tx.

WHAT DO YOU SEE?

cerebellum el paso tx.EYE MOVEMENT REVIEW

cerebellum el paso tx.

cerebellum el paso tx.WHAT CAN YOU DO?

  • cerebellum el paso tx.Have the patient perform gaze stability exercises:

  • Sit arms length away
  • Fixate on dot
  • Rotate head in different directions
  • Rotation exercises:

  • Activate VOR
  • Activate side less active
  • Provide OPK stimulation:

  • Which side do you stimulate?

CEREBROCEREBELLUM

cerebellum el paso tx.Responsibilities:

  • Coordination of fine movements
  • Coordination of speech
  • Coordination of thought
  • Patient Complaints:

  • Clumsiness with hands
  • Clumsiness with feet
  • Tripping over feet
  • Hand shaking with intention
  • Examination Findings:

  • Intention tremor
  • Termination tremor
  • Dysmetria
  • Dysdiadochokinesia

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

cerebellum el paso tx.http://www.neuroexam.com/neuroexam/content.php?p=37

WHAT DO YOU SEE?

cerebellum el paso tx.WHAT CAN YOU DO?

  • cerebellum el paso tx.Have the patient perform coordinated movements!
  • Example: piano playing, finger taping, finger to nose, etc.

 

 

 

 

 

 

 

TAYLOR ET AL. CUTTING YOUR NERVE CHANGES YOUR BRAIN BRAIN, 2009

  • �Animal studies have established that plasticity within the somatosensory cortex begins immediately following peripheral nerve transection, and that 1 year after complete nerve transection and surgical repair, cortical maps contain patchy, noncontinuous representations of the transected and adjacent nerves.�
  • �Here, we have demonstrated for the first time that there is functional plasticity and both grey and white matter structural abnormalities in several cortical areas following upper limb peripheral nerve transection and surgical repair.�

cerebellum el paso tx.

By�RYAN CEDERMARK, RN BSN MSN DC DACNB