Spine Health & Spinal Hygiene

Tremors are extremely rare, but they can result from spinal compression and not necessarily a brain condition like Parkinson's disease. Tremors are abnormal, involuntary body movements with various causes, most of which are connected to the brain and not the spine. A study reports that more than 75% of individuals with Parkinson's experienced a resting tremor, and about 60% experience tremors while moving. Sometimes the spine is the contributor caused by compression of the spinal cord.

Spinal Compression Study

A 90-year-old man was hospitalized after having tremors, with Parkinson's being the initial diagnosis. The tremors progressed to the point where the man could not feed himself or walk without support. The case became the focus of a medical report published by physicians in the Department of Orthopaedic Surgery, Division of the Spine, Singapore Tan Tock Seng Hospital. Along with the tremors, symptoms progressed to:

• Difficulty with fine motor skills like buttoning a shirt.
• However, it was ruled out because the patient was not presenting with other Parkinson's symptoms.
• What was found from the symptoms was cervical spondylotic myelopathy, which is a spinal cord compression in the neck.
• The compression was caused by a herniated disc impinging the spinal canal and compressing the spinal cord causing spinal stenosis.
• The compression was resolved by having an ACDF surgical procedure.
• An anterior cervical discectomy and fusion or ACDF procedure can help manage the condition.
• An ACDF treats spinal cord compression by removing a degenerative or herniated disc in the neck.

Cervical Myelopathy

Causes of cervical spondylotic myelopathy include:

• Trauma
• Infections
• Inflammatory diseases like rheumatoid arthritis.
• Spinal stenosis

Common symptoms include:

• Balance problems
• Coordination problems
• Tingling in the hands
• Numbness
• Weakness
• Impairment of fine motor skills

Tremors as a symptom are rare.

Cervical Myelopathy vs. Parkinson's Disease

There are cases where cervical spondylotic myelopathy and Parkinson's disease symptoms can overlap. Studies have shown difficulties between the two diagnoses, as well as, individuals with Parkinson's may exhibit symptoms similar to cervical spondylotic myelopathy that can include:

• Weakness
• Lack of coordination
• Bowel dysfunction
• Bladder dysfunction

Treatment Cervical Myelopathy Tremors

For individuals with cervical spondylotic myelopathy tremors, surgery can be used to help the condition. However, with cervical myelopathy, there is often some permanent damage. Individuals have shown that post-surgery and decompression, symptoms still present, maybe not as much, but there will be a need for a symptom management plan.

Prevention

The best way to prevent tremors associated with cervical spondylotic myelopathy is to minimize the strain on the spine that can lead to herniated discs and/or other spinal injuries. The discs in the spine degenerate, dry out and start cracking with age, increasing the risk of rupture. If a tremor develops, contact a doctor, spine specialist, or chiropractor to help diagnose the condition. These doctors can perform physical and neurological tests to determine the cause and treatment options.

Body Composition

Aging Health

Steady weight gain throughout life can lead to adult-onset diabetes. This is partly caused by having more body fat and progressive muscle loss. Loss of skeletal muscle mass is linked to insulin resistance that involves:

• The less muscle is available, the less insulin sensitive the body becomes.
• As insulin sensitivity decreases, the body becomes more resistant, increasing risk factors for type II diabetes.
• This can lead to osteoporosis, where the old bone is reabsorbed more and less new bone is created.

Both men and women can experience decreased muscle mass that can lead to:

• Thinner bones
• Weaker bones
• Increased risk of osteoporosis and severe injury from falls.

To help prevent these issues, it is recommended to:

• Eat sufficient protein throughout the day.
• It is recommended to space out protein intake across meals rather than consuming it all at once. This helps to ensure the proper amount is acquired.
• Monitoring body composition regularly can help minimize muscle mass loss and fat mass gain as the body ages.
• A regular strength training routine will help strengthen bones muscles and maintain optimal circulation.

General Disclaimer *

The information herein is not intended to replace a one-on-one relationship with a qualified health care professional, licensed physician, and is not medical advice. We encourage you to make your own health care decisions based on your research and partnership with a qualified health care professional. Our information scope is limited to chiropractic, musculoskeletal, physical medicines, wellness, sensitive health issues, functional medicine articles, topics, and discussions. We provide and present clinical collaboration with specialists from a wide array of disciplines. Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the injuries or disorders of the musculoskeletal system. Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate to and support, directly or indirectly, our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request.

We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.

Dr. Alex Jimenez DC, MSACP, CCST, IFMCP*, CIFM*, ATN*

email: coach@elpasofunctionalmedicine.com

Licensed in: Texas & New Mexico*

References

Heusinkveld, Lauren E et al. "Impact of Tremor on Patients With Early Stage Parkinson's Disease." Frontiers in neurology vol. 9 628. 3 Aug. 2018, doi:10.3389/fneur.2018.00628

Jancso, Z et al. "Differences in weight gain in hypertensive and diabetic elderly patients primary care study." The Journal of nutrition, health & aging vol. 16,6 (2012): 592-6. doi:10.1007/s12603-011-0360-6

Srikanthan, Preethi, and Arun S Karlamangla. "Relative muscle mass is inversely associated with insulin resistance and prediabetes. Findings from the third National Health and Nutrition Examination Survey." The Journal of clinical endocrinology and metabolism vol. 96,9 (2011): 2898-903. doi:10.1210/jc.2011-0435

Tapia Perez, Jorge Humberto et al. "Treatment of Spinal Myoclonus Due to Degenerative Compression Myelopathy with Cervical Spinal Cord Stimulation: A Report of 2 Cases." World neurosurgery vol. 136 (2020): 44-48. doi:10.1016/j.wneu.2019.12.170

Getting dizzy can happen, usually after standing up too fast or staring at an optical illusion then looking away. The unsteadiness can be troubling but is minimal when compared to vertigo symptoms. Vertigo is a symptom rather than a condition that causes dizziness combined with a spinning sensation, even when an individual stands completely still. Vertigo can make everyday life a debilitating nightmare:

• It causes individuals to feel nauseous.
• It makes it difficult to walk.
• It interrupts vision and hearing.

Vertigo symptoms usually begin with a communication issue with the inner ear and brain. This neurological connection involves the spinal cord, which chiropractic can treat and cure. A chiropractor will implement the necessary techniques to help alleviate vertigo symptoms.

Causes

The most common signs and symptoms are dizziness accompanied by a spinning sensation. Vertigo symptoms can also include:

• Balance issues
• Body swaying
• Headache/s
• Tinnitus
• Sweating
• Nausea
• Vomiting

Vertigo is a common symptom in individuals that have gone through trauma to the neck and/or head. A  disturbance/interruption occurs in the nerve pathways in the spinal column. Disruption, injury, or damage to the vestibular system/inner ear also causes vertigo symptoms. Other causes include:

• Ear infections
• Pressure changes
• Movement of particles within the inner ear

Chiropractic Treatment

Chiropractic treatment can cure vertigo symptoms through various exercises and spinal adjustments. When nerve signals don't transmit correctly, it can cause a feeling of dizziness along with the other symptoms. Adjustments or manipulations help alleviate the symptoms by allowing nerve energy to circulate properly. Spinal adjustments realign the joints and vertebrae in the cervical spine. This opens the nerves pathways and allows for clear communication.

A common type of vertigo is known as benign paroxysmal positional vertigo or BPPV. This is the movement of particles around the inner ear. These particles come from otolith organs. The particles break loose and fall into other parts of the vestibular labyrinth. This alters the center of balance and can cause dizziness. A chiropractor may use the Epley maneuver, which maneuvers the head into different positions. A chiropractor will recommend specific exercises at home to benefit the vestibular system and its communication with the brain.

Body Composition

A Common Cold

The common cold, aka upper respiratory tract inflammation. It is the most common infectious respiratory disease. It is called this because of the effects on the nose and throat. According to the Center for Disease Control and Prevention, an adult will catch 2–3 colds a year. A cold-causing virus enters the respiratory tract directly when an individual inhales droplets or direct skin contact from an infected person. Cold symptoms include:

• Runny nose
• Stuffy nose
• Sneezing
• Coughing
• Headaches
• Body aches

The duration of a cold differs, but most individuals with a healthy immune system recover in 7–10 days. However, individuals with compromised immune systems, asthma, or COPD have an increased risk of developing serious illnesses like bronchitis or pneumonia. Quickly recovering from a cold requires boosting the immune system with proper rest, a nutritious diet, and drinking plenty of water. 

General Disclaimer *

The information herein is not intended to replace a one-on-one relationship with a qualified health care professional, licensed physician and is not medical advice. We encourage you to make your own health care decisions based on your research and partnership with a qualified health care professional. Our information scope is limited to chiropractic, musculoskeletal, physical medicines, wellness, sensitive health issues, functional medicine articles, topics, and discussions. We provide and present clinical collaboration with specialists from a wide array of disciplines. Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the injuries or disorders of the musculoskeletal system. Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate to and support, directly or indirectly, our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request.

We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.

Dr. Alex Jimenez DC, MSACP, CCST, IFMCP*, CIFM*, ATN*

email: coach@elpasofunctionalmedicine.com

Licensed in: Texas & New Mexico*

References

Collins, Matthew E, and Tom M Misukanis. “Chiropractic management of a patient with post-traumatic vertigo of complex origin.” Journal of chiropractic medicine vol. 4,1 (2005): 32-8. doi:10.1016/S0899-3467(07)60110-4

Dalby, B J. “Chiropractic diagnosis and treatment of closed head trauma.” Journal of manipulative and physiological therapeutics vol. 16,6 (1993): 392-400.

Sajko, Sandy S et al. “Chiropractic management of benign paroxysmal positional vertigo using the Epley maneuver: a case series.” Journal of manipulative and physiological therapeutics vol. 36,2 (2013): 119-26. doi:10.1016/j.jmpt.2012.12.011

The spinal cord and brain make up the central nervous system while the spinal nerves (branching to the spinal cord) and cranial nerves (branching to the brain) make up the peripheral nervous system.

There are 31 sets of nerves that extend out of the spinal cord and are connected to it by the nerve root. Each nerve branches out about a half inch from the spinal cord before dividing into smaller branches. The dorsal rami are on the posterior side of the branch while the larger ventral rami are on the anterior side.

The dorsal rami provide nerve function for the skin of the trunk and posterior muscles. The ventral rami from T1 to T12 provide nerve function to the skin of the trunk as well as the lateral and anterior muscles. The anterior divisions that remain for plexuses, networks that provide nerve function to the body.

Each plexus has specific areas on the body for skin sensitivity as well as certain muscles. Their point where they exit the spine determines how they are numbered. The four primary plexuses are:

• Cervical plexus, C1 – C4, innervates the diaphragm, shoulder, and neck
• Brachial plexus, C5 – T1, innervates the upper limbs
• Lumbar plexus, T12/L1 – L4, innervates the thigh
• Sacral plexus, L4 – S4, innervates the leg and foot.

These spinal nerves have two sets of fibers: motor and sensory. Motor fibers facilitate movement and provide nerve function to the muscles. Sensory fibers facilitate sensitivities to touch, temperature and other stimuli. They provide nerve function to the skin.

What are Myotomes and Dermatomes?

A group of muscles that are innervated by the motor fibers that stem from a specific nerve root is called a myotome. An area of the skin that is innervated by the sensory fibers that stem from a specific nerve root is called a dermatome. These patterns of myotome and dermatome are almost always identical from person to person. There are occasionally variances, but that is rare.

This consistency allows doctors to treat nerve pain in patients. If a certain area is hurting, they know that it is attributed to a certain myotome or dermatome, whichever the case may be, and its corresponding nerve root. Problems with nerve damage are often the result of stretching the nerve or compressing it.

When the nerves are injured in specific areas like the lumbosacral or brachial plexus, it presents as sensory and motor deficits in the limbs that correspond to them. Myotomes and dermatomes are used to assess the extent of the damage.

How are Myotomes and Dermatomes used to Assess Nerve Damage? 

When a doctor tests for nerve root damage in a patient, he or she will often test the myotomes or dermatomes for the nerves assigned to that location. A dermatome is examined for abnormal sensation, such as hypersensitivity or lack of sensitivity.

This is done by using stimulus inducing tools such as a pen, paper clip, pinwheel, fingernails, cotton ball, or pads of the fingers. The patient is instructed to provide feedback regarding their response. Some of the abnormal sensation responses include:

• Hypoesthesia (decreased sensation).
• Hyperesthesia (excessive sensation).
• Anesthesia (loss of sensation).
• Paresthesia (numbness, tingling, burning sensation).

A myotome is tested for nerve damage in the muscles which presents as muscle weakness. This grading scale, which assigns a rating to the degree of muscle weakness, is often used:

• 5 – Normal – Complete range of motion against gravity with full resistance
• 4 – Good – Complete range of motion against gravity with some resistance
• 3 – Fair – Complete range of motion against gravity with no resistance, active ROM
• 2 – Poor – Complete range of motion with some assistance and gravity eliminated
• 1 – Trace – Evidence of slight muscular contraction, no joint motion evident
• 0 – Zero – No evidence of muscle contraction

During a typical chiropractic exam, your chiropractor will assess both dermatomes and myotomes for potential neurological problems. This gives him or her additional insight on how to treat your condition, whether it's related to a subluxation of vertebral bodies or other other disease processes.

Back Pain Chiropractic Care | El Paso, Tx

Ataxia is a degenerative disease of the nervous system. Symptoms can mimic those of being inebriated/intoxicated, with  slurred speech, stumbling, falling, and unable to maintain coordination. This comes from degeneration of the cerebellum, which is the part of the brain responsible for coordinating movement. It is a disease that affects people of all ages. However, age of symptom onset can vary, from childhood to late adulthood. Complications from the disease can be serious, even debilitating and life shortening.

Symptoms can vary from person to person, as well as, the type of Ataxia. Symptom onset and progression can vary as well. Symptoms can worsen slowly, over decades or quickly, over a few months. The common symptoms are lack of coordination, slurred speech, trouble eating, swallowing, eye movement abnormalities, motor skill deterioration, difficulty walking, gait abnormalities, tremors, and heart problems. People with Ataxia usually require wheelchairs, walkers, and/or scooters to aid in mobility.

Ataxia

The Loss Of Full Control Of Bodily Movements, Especially Gait

History Of Ataxia

• How long has it been present?
• Slow onset ➔ Degenerative disease?
• Acute onset ➔ Stroke?
• When does it occur?
• If worsened by walking on uneven surfaces, or with limited vision ➔ Sensory ataxia?
• Are there any coexisting symptoms?
• Vertigo, weakness, stiffness, cognitive changes, etc.
• Have others noticed this gait disturbance?
• If no, consider psychogenic cause
• Is the gait change explainable by physical problems such as pain or weakness?
• Antalgic gait, limp, etc.

• Weakness

• Proximal muscle weakness ➔ Myopathy?
• Distal muscle weakness ➔ Neuropathy?
• UMN signs?
• LMN signs?
• Has the patient fallen? Or at risk for fall?
• Is ataxia limiting ADLs?

Balance

• Utilizes
• Vestibular system
• Cerebellar system
• Conscious proprioceptive information (joint position sense)
• Visual information
• Motor strength and coordination

Vestibular System

• Generally, if the problem lies in the vestibular system the patient will experience dizziness, possibly having vertigo or nystagmus
• Unable to walk a straight line
• When walking, will tend to veer to one side

Testing The Vestibular System

• Fukuda Stepping Test

• Patient marches in place with eyes closed and arms raised to 90 degrees in front of them
• If they rotate more than 30 degrees = positive
• Patient will rotate toward the side of vestibular dysfunction

• Rhomberg Test

• If patient sways a different direction every time their eyes are closed, this may indicate vestibular dysfunction

Cerebellar System

• Cerebellar gaits present with a wide-base and generally involve staggering and titubation
• Patient will have difficulty doing Rhomberg’s test with eyes open or closed, because they cannot stand with their feet together
• Afferent information helps make assessments about where the body is in space
• Ventral spinocerebellar tract
• Dorsal spinocerebellar tract
• Cuneocerebellar tract
• Olivocerebellar tract
• Efferent tracts carry responsive information to make adjustments to muscle tone and position to maintain balance

Testing The Cerebellar System

• Piano-playing test & hand-patting test

• Both assess for dysdiadochokinesia
• Both tests, patient will have more difficulty moving the limb on the side of cerebellar dysfunction

• Finger-to-nose test

• Patient may be hyper/hypo metric in movement
• Intention tremor may be reveled

Joint Position Sense

• Conscious proprioception may be diminished, especially in elderly patients and patients with neuropathy

Visual Information

• Patients with joint position sense losses often rely on visual information to help compensate.
• When visual input is removed or diminished these patient’s have exaggerated ataxia.

Motor Strength & Coordination

• If patient has reduced frontal lobe control they may end up with an apraxia of gait, where they have difficult with the volitional control of movement
• Extrapyramidal disorders such as Parkinson disease result in inability to control motor coordination
• Pelvic girdle muscle weakness due to a myopathy will produce an abnormal gait pattern

Commonly Seen Abnormal Gait Patterns

• Circumduction gait

• Hemiplegia
• Often due to stroke
• Bilaterally (Diplegic gait), causes toe walking
• Typical gait of cerebral palsy patients

• Festinating gait

• Small steps due to spasticity
• Often seen in Parkinson Disease

• Myopathicgait(waddling)

• Seen in disorders of proximal muscle weakness

• Steppage gait/Neuropathic gait

• Leg is lifted from the hip, without dorsiflexion at the ankle
• Often seen in patients with foot-drop due to a LMN lesion
• Wide-BasedCerebellargait

Gait Deviation/Examination Videos

Gait Deviations 2012

Gait Examination (Stanford Medicine 25) 

Dizziness

The Sensation Of Loss Of Balance

• 4 Main Types

• Vertigo
• Peripheral
• Central
• Pre-Syncope/Light-headedness
• Disequilibrium
• Other/Floating type

Peripheral Vertigo

• More common than central vertigo
• Due to damage to the inner ear or CN VIII
• Usually produces abnormal eye movements
• Nystagmus – May be horizontal or rotary
• Usually jerky in nature, with a fast and slow phase
• Named for the direction of the fast phase
• Vertigo usually worsens when patient looks to the side of the fast phase of nystagmus
• Severity of nystagmus usually correlates with severity of vertigo
• No other symptoms/signs of CNS dysfunction
• Patient may have nausea or difficulty walking, but only because of vestibular dysfunction
• Patient may also have hearing loss or tinnitus due if CN VIII or auditory mechanism function is damaged
• Typically the causes are benign, including
• Benign paroxysmal positional vertigo (BPPV)
• Cervicogenic vertigo
• Acute labyrinthitis/Vestibular neuronitis
• Meniere’s Disease
• Perilymph fistula
• Acoustic Neuroma

Narrowing It Down

• If movement, particularly of the head/neck exacerbate vertigo, consider:
• BPPV
• Vertebrobasilar artery insufficiency
• Cervicogenic vertigo
• If noise brings on episodes, consider:
• Meniere’s disease
• Perilymph fistula

Vertigo Hx Questions

• Does your dizziness feel like you’re on an amusement park ride?
• Do you get nauseous when you’re dizzy?
• Are you spinning?
• Or is the world spinning?

Benign Paroxysmal Positional Vertigo (BPPV/BPV)

• May develop spontaneously, especially in the elderly
• May arise due to head trauma
• Vertiginous episodes associated with specific movements:
• Looking at a high shelf (“top-shelf vertigo”)
• Bending over
• Rolling over in bed
• Onset of vertigo begins a few seconds after the movement, and resolves within about a minute
• Diagnostic test
• Dix-Hallpike Maneuver
• Treatment procedure
• Epley Maneuver
• Brandt-Daroff Exercises
• Can self resolve as crystals dissolve, but it may take months and new otoliths can become displaced

Cervicogenic Vertigo

• Occurs after head/neck injuries, but is not very common
• Usually accompanied by pain and/or joint restriction
• Usually vertigo and nystagmus will be less severe than in BPPV
• Vertigo begins with change in head position but does not subside as quickly as it does in BPPV

Vertebrobasilar Artery Insufficiency

• Occurs if the vertebral artery is compressed during head rotation/extension
• Onset of vertigo is delayed more than in BPPV or cervigogenic vertigo, because ischemia will take up to 15 seconds to occur
• Orthopedic test may help in evaluation
• Barré-Liéou Sign
• DeKlyn Test/Hallpike Maneuver
• Hautant test
• Underberg Test
• Vertebrobasilar After Functional Maneuver

Acute Labyrinthitis/ Vestibular Neuronitis

• Not well understood, but believed to be inflammatory in origin
• Follows viral infection or arise seemingly without cause
• Single, monophasic attack of vertigo
• Resolves in days to a few weeks and generally does not reoccur

Meniere’s Disease

• Increased pressure in the endolymph causes membrane ruptures and sudden mixture of endolymph and perilymph
• Episodes last 30 minutes to several hours, until equilibrium between the fluids is reached
• Over time, episodes damage vestibular and cochlear hair cells
• Low-pitch buzzing tinnitus
• Loss of hearing of low tones

Meniere’s Disease vs. Syndrome

• Meniere’s syndrome is when then symptoms of Meniere’s disease are found to be secondary to another condition, such as:
• Hypothyroidism
• Acoustic neuroma
• Superior semicircular canal dehiscence (SCDS)
• Perilymph fistula
• True Meniere’s disease is idiopathic

Perilymph Fistula

• Small leak due to trauma, especially barotrauma
• Can look very similar symptomatically to Meniere’s disease/syndrome
• Exacerbated by changes in pressure
• Airplane rides
• Driving uphill
• Hennebert’s sign
• Vertigo or nystagmus episode brought on by sealing pressure of the ear (such as by inserting an otoscope)

Central Vertigo

• Less common than peripheral vertigo
• Caused by damage to the processing centers of vestibular information in the brain stem and the cerebral cortex
• Typically “dizziness” is less severe than with peripheral vertigo
• Nystagmus
• Usually more severe than the description/patient’s complaint
• May go in multiple directions, including vertical
• May or may not have other CNS findings on examination
• No change in hearing expected

Causes Include:

• Cerebrovascular disease (such as transient ischemic attacks)
• Multiple Sclerosis
• Arnold-Chiari Malformation
• Damage to caudal brainstem or vestibulocerebellum
• Migraine condition

Pre-Syncope Hx Qustions

• Does it feel like you’re going to pass out?
• Does the dizziness feel similar to when you stand up too fast?

Pre-Syncope

• “Light-headedness”
• CardiacOrigin
• Output disorders
• Arrhythmias
• Holter monitor testing
• Postural/Orthostatic hypotension
• May be secondary to other problems (diabetic neuropathy, adrenal hypofunction, Parkinsons, certain medications, etc.)
• Vasovagal episodes
• Slow heart rate with low blood pressure
• Often brought on by stress, anxiety or hyperventilation
• Migraine
• Due to cerebrovascular instability
• Blood sugar dysregulation

Disequilibrium Hx Questions

• Does the dizziness only occur when you’re on your feet?
• Does it get better if you touch/hold onto something?

Disequilibrium

• Common in the elderly
• Due to sensory deficits
• Gradual onset
• Worsened by reduced vision
• Dark
• Eyes closed
• Visual acuity losses
• Improved by touching a stationary object
• Subjective of dizziness often improves with a gait assistive device (cane, walker, etc.)

Other Causes

• Psychological stress
• Often patient will describe dizziness as “floating”
• Rule out hyperventilation and other types of dizziness

Sources

Blumenfeld, Hal. Neuroanatomy through Clinical Cases. Sinauer, 2002.
Alexander G. Reeves, A. & Swenson, R. Disorders of the Nervous System. Dartmouth, 2004.

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.

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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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

• “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.”

THE CEREBELLUM

IMPORTANT FUNCTIONAL AREAS OF THE CEREBELLUM

• Spinocerebellum

• Vestibulocerebellum

• Cerebrocerebellum 

SPINOCEREBELLUM

• 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

http://www.neuroexam.com/neuroexam/content.php?p=37

WHAT DO YOU SEE?

WHAT CAN YOU DO?

• 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

• 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

http://www.neuroexam.com/neuroexam/content.php?p=37

VOR

WHAT DO YOU SEE?

EYE MOVEMENT REVIEW

WHAT CAN YOU DO?

• 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

• 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

http://www.neuroexam.com/neuroexam/content.php?p=37

WHAT CAN YOU DO?

• 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.”

By RYAN CEDERMARK, RN BSN MSN DC DACNB

Gastrointestinal stress and digestion issues/problems have become a familiar experience for many individuals. Gastrointestinal issues include:

• Dyspepsia or indigestion 
• Bloating
• Gas
• General abdominal pain
• Irritable bowel syndrome IBS
• Crohn's Disease
• Constipation
• Diarrhea
• Persistent stomach pains

All of these can deplete the body of nutrients and drain the body's energy. As a result, individuals can be distracted throughout the day, unable to leave the house, and unable to accomplish regular tasks. Gastrointestinal stress can be caused by a variety of factors, including:

• Unhealthy diet
• Interrupted sleep patterns
• Work/school changes
• Headaches
• Medications
• Fibromyalgia

Digestive issues are commonly associated with poor nutrition, but there could be an underlying cause in the spine and nervous system. Chiropractic can help manage gastrointestinal stress and stomach problems.

Spinal Subluxation and Gastrointestinal Stress

The nervous system controls every function that the body performs, including digestion. The spine communicates with the stomach directly. The thoracic mid-back and lumbar low-back regions of the spine are responsible for regulating the rate of how food is physically broken down and digested. A subluxation or spinal misalignment can interfere with vital information transmissions from the brain to the digestive tract compromising digestive function.

Subluxation

Subluxation refers to a misalignment of the vertebrae that can cause health issues with the nerves in the spine, directly affecting digestion. If the vertebrae are out of alignment, this causes a misfire in the signals being sent to the nerves of the digestive system.  This can cause problems for the body absorbing nutrients, vitamins, and minerals from food. Because of this, no matter how healthy the diet is, individuals can still suffer from digestive issues.

Chiropractic

Many individuals deal with stress through meditation, breathing exercises, physical activity/exercise, and diet adjustments.

Lifestyle adjustments help counter the effects of stress, but if the nervous system is blocked from spinal misalignment, disrupting vital nerve flow through the body, specifically the digestive tract, gastrointestinal stress will continue to cause damage and malfunction. Individuals with:

• Crohn's Disease
• Acid Reflux
• GERD
• IBS
• Have experienced how chiropractic treatment corrects and helps manage symptoms.

Body Composition

Viscous and Nonviscous Fiber

Another way of classifying fiber is by its viscosity or thickness. Certain types of soluble fiber are thicker and are more likely to form firmer, stickier gels when mixed with water. When digesting food that consists of thick fiber it increases the thickness of the gel substance that passes through the gut. As a result, it reduces appetite because it makes the body feel fuller longer. Viscous fibers include:

• Pectins - abundant in berries and fruits.
• β-Glucans - Beta-glucans - abundant in barley and oats.
• Guar gum - derived from the Indian cluster bean.
• Psyllium - derived from psyllium seed husks.

The most frequently cited benefits of fiber include:

• Reduces cholesterol levels
• Improves glycemic control in type 2 diabetes
• Improves stool form in constipation and diarrhea directly related to viscosity.

Nonviscous food sources tend not to have these benefits. A recommended strategy is to lean toward foods higher in viscosity.

General Disclaimer *

The information herein is not intended to replace a one-on-one relationship with a qualified health care professional, licensed physician, and is not medical advice. We encourage you to make your own health care decisions based on your research and partnership with a qualified health care professional. Our information scope is limited to chiropractic, musculoskeletal, physical medicines, wellness, sensitive health issues, functional medicine articles, topics, and discussions. We provide and present clinical collaboration with specialists from a wide array of disciplines. Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the injuries or disorders of the musculoskeletal system. Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate to and support, directly or indirectly, our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request.

We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.

Dr. Alex Jimenez DC, MSACP, CCST, IFMCP*, CIFM*, ATN*

email: coach@elpasofunctionalmedicine.com

Licensed in: Texas & New Mexico*

References

Angus, Katherine et al. “What effect does chiropractic treatment have on gastrointestinal (GI) disorders: a narrative review of the literature.” The Journal of the Canadian Chiropractic Association vol. 59,2 (2015): 122-33.

Qu, Liuxin et al. “Irritable bowel syndrome treated by traditional Chinese spinal orthopedic manipulation.” Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan vol. 32,4 (2012): 565-70. doi:10.1016/s0254-6272(13)60072-2

Spinal meningitis does not just affect the brain. Most think of meningitis as a brain disease, but it can also affect the spine. We will discuss learning how to recognize it and find the right treatment to fix it within the spinal cord. Spinal meningitis can be a potentially deadly infection of the meninges. This is the protective tissue that covers the brain and spinal cord.

It can be caused by viruses, bacteria, or fungi that are transmitted from person to person by sneezing, talking, and sharing food. Viruses and pathogens that cause other infections, like the mumps and measles, can also cause meningitis. The lining around the brain and the spine are connected, which means that infection can travel from one area to another, or remain in the brain or the spine. 

The Meninges

Meninges are the protective membranes that surround the brain and spinal cord. They are made up of three layers:

• Dura mater is the thick and tough outer layer
• Arachnoid mater is the middle layer made up of strands of connective tissue
• Pia mater is the inner layer of cells

Spinal meningitis can develop when a virus, bacteria, or pathogen invade the meninges layers. This causes the immune system to react trying to remove the invading bacteria etc, which causes inflammation. These organisms usually take up residence in the nose and throat and never cause problems. Most individuals that come into contact with these viruses never get sick.

The reason for this is because the body produces fighting antibodies before the pathogens can invade the meninges. Others, possibly from age or underlying conditions, where they are not able to produce enough or any antibodies, makes them vulnerable to the illness. When the brain and spine's tissue/s get infected with any one of these pathogens, the tissue swells, which constricts proper blood flow to the brain.

Types of Spinal Meningitis

The most common types of spinal meningitis in the United States include:

Viral meningitis

Viral meningitis is caused by enteroviruses, which are common viruses that enter the body through the mouth and travel to the brain and tissues where multiplication ensues. There are other viruses that can also cause meningitis. These include:

• Viruses that cause mumps
• Herpesviruses - like Epstein-Barr, measles, influenza, West Nile
• Lymphocytic choriomeningitis virus from rodents

Any of these viruses can spread to the meninges, causing spinal meningitis to develop. This is a less severe type than bacterial meningitis.

Bacterial meningitis

This is the type where dangerous bacteria invade the meninges. Individuals are at higher risk as this type can be fatal if not treated. Common types of bacterial meningitis include:

• Haemophilus influenzae - can cause severe infection/s of the lining of the brain, spinal cord, and the blood.

• Pneumococcal meningitis - is caused by the bacterium Streptococcus pneumonia and is the most common form of bacterial meningitis.

• Meningococcal meningitis - also known as meningococcal disease, is a less common type. This type is caused by the bacterium Neisseria meningitides. Around 2,600 people in the U.S. are affected yearly.

Symptoms

Viral or bacterial spinal meningitis can cause a range of symptoms, including:

• Neck and back stiffness
• Muscle weakness
• Headache
• Drowsiness
• Fatigue
• Fever
• Double vision
• Sensitivity to light
• Nausea
• Vomiting
• Hearing difficulty
• Confusion
• Seizures
• Rash

Symptoms are often far more pronounced with the bacterial form. This is because it’s associated with more inflammation, compared to the viral type.

Complications

Depending on the type whether viral or bacterial the results can be serious, leading to:

• Permanent brain damage
• Permanent organ damage
• Stroke
• Loss of hearing
• Loss of limbs
• Death

Anyone who experiences symptoms of meningitis should see a doctor immediately for diagnosis and treatment options.

The risk for Spinal Meningitis

Getting spinal meningitis depends on various factors like:

• Age
• Immune system status
• If the individual lives in a group environment
• Children younger than five
• Individuals with weakened immune systems from taking medication/s for other conditions
• Recent organ/bone marrow transplants
• Babies younger than 1-month-old along with weakened immune systems are more likely to experience severe illness

These are factors that could increase the risk of viral meningitis. Fortunately, most cases are not serious and in children's cases, most recover in one to two weeks. Meningitis can also occur very rarely after spine surgery where the lining around the dura is torn with an infection happening at the same time.

Diagnosis

Detecting spinal meningitis a doctor will utilize:

• Blood tests
• Imaging tests
• Spinal tap to test the cerebrospinal fluid which surrounds the brain and spinal cord.
• The fluid is collected and sent to a lab, where it is analyzed for bacteria or viruses.

Treatment

Antiviral medication can help with certain types of viral meningitis with other meds for treating meningitis symptoms. Doctors recommend bed rest, proper fluids, and medication for fever relief and headache relief. This is for viral meningitis.

Antibiotic medications can treat bacterial spinal meningitis. It is commonly treated with intravenous antibiotics in a hospital setting. Unfortunately, around ten percent of children with bacterial meningitis die from it yearly. Even with immediate antibiotic treatment a child's body can become overwhelmed by the bacteria/organism. The Meningococcus bacteria can create a toxin that invades the blood. This can be fatal for a child or adolescent within hours. This is why it’s highly recommended to prevent bacterial meningitis than to treat it once it's active.

Contagious

Proper hygiene like hand washing, not sharing food, beverages, utensils, or body care products like lip salve/balm can help stop the spread of bacterial and viral meningitis.

Chiropractors On Metabolic Syndrome & Inflammation

Dr. Alex Jimenez’s Blog Post Disclaimer

The scope of our information is limited to chiropractic, musculoskeletal, physical medicines, wellness, and sensitive health issues and/or functional medicine articles, topics, and discussions. We use functional health & wellness protocols to treat and support care for injuries or disorders of the musculoskeletal system. Our posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate and support directly or indirectly our clinical scope of practice.*

Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. We understand that we cover matters that require an additional explanation as to how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900. The provider(s) Licensed in Texas& New Mexico*

Cerebrovascular disease is a designated group of conditions that can lead to cerebrovascular event/s, i.e. stroke. These events affect the blood supply and vessels to the brain. With a blockage, malformation, or hemorrhage happens, this prevents brain cells from getting enough oxygen, which can cause brain damage. Cerebrovascular diseases can develop in different ways. These include deep vein thrombosis (DVT) and atherosclerosis.

Types of cerebrovascular disease: Stroke, transient ischemic attack, aneurysms, and vascular malformations.

In the U.S. cerebrovascular disease is the fifth most common cause of death.

Cerebrovascular Disorders

The Brain

• Makes up ~2% of the body weight
• Accounts for ~10% of the body’s oxygen use
• Accounts for ~20% of the body’s glucose use
• Receives ~20% of the cardiac output
• Per minute, requires ~50-80cc of blood per 100g of grey matter brain tissue and ~17-40cc of blood per 100g of white matter
• If blood supply to the brain is <15cc per 100g of tissue, per minute, neurologic dysfunction occurs
• As with all tissues, the longer there is ischemia, the more likely there is to be cell death and necrosis
• The brain depends on a constant, uninterrupted supply of oxygen and glucose
• 3-8 minutes of cardiac arrest can result in irreversible brain damage!

Autoregulation In The Brain

• Systemic hypotension causes reactive cerebral vasodilation to allow more blood flow to the brain
• The brain can extract enough oxygen from the brain if systolic pressure is 50 mmHg
• Atherosclerotic narrowing can produce reactive vasodilation to attempt to reduce excess pressure
• Increased blood pressure can result in vasoconstriction, reducing likelihood of hemorrhage
• If systolic pressure averages >150 mmHg for prolonged periods, this compensation may fail
• Labelled hypertensive encephalopathy

Blood Supply To The Head

http://madeinkibera.com/lingual-arterie-anatomie

Collateral Circulation

• In slowly developing occlusion such as atherosclerotic thrombosis, collateral circulation has time to develop
• Circle of Willis connects the carotid and basilar systems
• Anterior and posterior communicating arteries provide collateral supply
• Anastomoses between main cerebral and cerebellar arteries in some people
• Internal and external carotid artery connection via the ophthalmic & maxillary arteries

Circle Of Willis

• Connects the vertebrobasilar system with the internal carotid system
• While providing helpful collateral circulation, is also the most susceptible area to Berry Aneurysms which can lead to hemorrhagic stroke

https://en.wikipedia.org/wiki/Circle_of_Willis

Blood Supply To The Brain

http://teachmeanatomy.info/neuro/vessels/arterial-supply/

Maxillary & Ophthalmic aa.

https://www.earthslab.com/anatomy/supratrochlear-artery/

Cerebrovascular Disorders

• ~700,000 adults in the US have a stroke each year
• Third most common cause of death in the US
• ~2 million people are disabled due to stroke
• By far more common in persons of advanced age
• Occlusive/Ischemic Disease
• 80% of all strokes
• Most common site of occlusion is at the internal carotid artery just above the bifurcation of the common carotid a.
• Atherothrombotic
• Embolic
• Small vessel
• Hemorrhagic Disease

Occlusive/Ischemic Stroke

• Can be due to artery OR vein occlusion
• Artery occlusion is much more common
• Due to lack of blood & oxygen supply reaching a particular area of the brain
• Sudden onset of neurologic deficits, correlating to the distribution of a specific artery
• Deficits will differ depend on which artery’s distribution has been disrupted

Venous Occlusion

• Hyperviscocity
• Dehydration
• Thombocytosis
• Elevated red or white blood cells counts
• Polycythemia
• Hypercoagulability
• Elevated homocysteine
• Prolonged immobility or airplane travel
• Genetic clotting factor disorders
• Pregnancy
• Cancer
• Hormone replacement & OCP use

Atherothrombotic

• Neurologic deficits may be transient or develop slowly over time
• Possible causes/types:
• Dissection of the tunica intima and tunica adventitia
• Can occur in younger patients with connective tissue disorders
• Inflammatory materials deposit & build up in the vessel walls
• Oxidized LDLs deposit in vessel walls

Embolic

• Neurologic deficits likely to have sudden onset
• Dislodged tissue from dissection of the tunica intima and tunica adventitia
• Any dislodged thrombus can become an embolus blocking/closing the lumen of smaller vessels

Small Vessel

• Lipohyalinosis
• Vessel wall micro-trauma & ballooning
• Amyloid Angiopathy
• Accumulation of amyloid proteins in vessel walls
• More common in patients >65 years old
• Causes narrowing (leading to ischemia) but can also cause vessel fragility (leading to hemorrhage)
• Associated with Alzheimer’s disease
• Inflammatory
• Spasmotic

Risk Factors For Occlusive Stroke

• Hypertension
• Diabetes Mellitus
• Cardiac abnormalities
• Right-left shunts (Patent foramen ovale, VSD, tetralogy of fallot, etc)
• Atrial fibrillation
• Valve disease/artificial heart valves
• Advanced age
• Obesity
• Hyperlipidemia
• Especially high LDL and low HDL
• Sedentary lifestyle
• Cigarette/Tobacco smoking
• High oxidation status
• Elevated homocysteine
• Contributed to by low folic acid, B6 & B12 statuses
• Interacts with LDL cholesterol
• Hyperviscocity and hypercoagulability states as shown on previous slide

Transient Ischemic Attack (TIA)

• Fully reversible episodes of neurologic deficit due to vascular insufficiency generally lasting no more than 30 minutes at a time
• Occasionally can last 24 hours or more
• Half of patients who suffer from a complete occlusive stroke previously had transient ischemic attack(s)
• 20-40% of patients with TIA go on to have complete stroke
• In is important to identify patients with TIAs to that they can be appropriately managed and modifiable risk factors reduced

History of Transient Neurologic Deficit In Patient > 45 y/o

• DDx
• TIA most likely dx
• Migraine
• Focal seizures
• BPPV
• Meniere’s
• Demyelinating diseases
• Temporal arteritis
• Hypoglycemia
• Tumor
• Arteriovenous malformations

Carotid Artery Disease

• High pitched systolic bruit heard over the carotid artery may indicate carotid stenosis
• Requires duplex ultrasound evaluation
• Lesions narrowing the lumen >70% can possibly cause ischemia
• Many carotid occlusions do not cause ischemia due to slow development allowing for collateral circulation to be developed as well
• Fast forming occlusions or emboli can produce problems with <70% stenosis
• Surgical intervention should be considered for patients with >70% stenosis and symptoms of TIA

Occlusive Stroke

• If there is an onset of definitive substantial neurologic deficit, the patient should have a CT to rule out hemorrhage
• If hemorrhage is ruled out, tissue plasminogen activator should be given within the first 4.5 hours
• It should not be given later than this because it can increase risk of bleeding during reperfusion of brain tissue
• After this initial period, focused thrombolysis or mechanical extraction of the embolus

Intracranial Hemorrhage

• Approximately 20% of stroke cases
• Severe HA or vomiting suggest hemorrhage over occlusion
• Two types
• Spontaneous intracranial hemorrhage
• Hypertension
• Arterial aneurysms
• Arteriovenous malformations
• Bleeding disorders
• Vessel weakening due to amyloid angiopathy
• Traumatic

Aneurysm Sites

• Intraparenchymal hemorrhage
• 50% - Lenticulostriate branches of the middle cerebral artery
• Affects the putamen and external capsule
• 10% - Penetrating branches of the posterior cerebral artery
• Affects the thalamus
• 10% - Penetrating branches of the superior cerebellar artery
• Affects the cerebellum
• 10% - Paramedian branches of the basilar artery
• Affects the basilar pons
• 20% - Various vessels affecting areas of white matter
• Subarachnoid hemorrhage
• Berry aneurysms at communicating artery junctions

Bleeding Disorders

• Thrombocytopenia
• Leukemia
• Excess anticoagulant therapies

Risk Factors For Hemorrhagic Stroke

• Hypertension
• Arterial aneurysms
• Arteriovenous malformations
• Bleeding disorders
• Vessel weakening due to amyloid angiopathy
• Head trauma

Signs Of Stroke: Teach Patients F.A.S.T

http://chrcsf.org/expert-tips-to-help-with-detecting-the-early-signs-of-stroke/

Common Transient Symptoms

• Vertigo
• Bilateral blurring or loss of vision
• Ataxia
• Diplopia
• Bilateral or unilateral sensory and motor deficits
• Syncope
• Weakness in the distribution of a motor cranial nerve one side of the head with a contralateral hemiparesis (medial brainstem damage)
• Damage to a sensory cranial nerve & Horner’s syndrome on one side of the head and loss of contralateral pain and temperature sensation in the body (lateral brainstem damage)

Long-Term Symptoms Depend On Area Affected

• Monocular visual obscuration (amaurosis fugax) that is due to retinal ischemia
• Contralateral hemiparesis
• Hemisensory deficit
• Visual field deficits
• Dysphasia
• Receptive aphasia (Wernicke’s area lesion)
• Expressive aphasia (Broca’s areas lesion)
• Contralateral neglect (on-dominant parietal lobe lesion)
• Problemswithinitiationofmovement(Supplementarymotorcortex lesion)
• Difficulty with voluntary gaze to the contralateral side (Frontal eye field lesions)
• Short-term memory deficits(medial temporal lobes lesioned)

Brain-Stem Syndromes

http://roho.4senses.co/stroke- syndromes/common-stroke- syndromes-chapter-9-textbook-of- stroke-medicine.html

Stroke Recovery

• Rehab needs depend upon the area of brain tissue that was affected by the stroke
• Speech therapy
• Restriction of functioning limbs
• Balance and gait exercises
• Encourages neuroplastic restructuring
• Symptoms may improve within the first 5 days due to reduction in edema
• Edema may cause herniation through the foramen magnum which can cause brainstem compression and death – patients with this problem may require craniectomy (last resort)

Sources

Alexander G. Reeves, A. & Swenson, R. Disorders of the Nervous System. Dartmouth, 2004.
Swenson, R. Cerebrovascular Disorders. 2010

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.

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.

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)

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.

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.

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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