# Presentation: 486922

## Traumatic Brain Injury and Pain

**F.Antonio Luque, M.D. Ph.D.**
**Neurology **

## Traumatic Brain Injury

**TBI in the USA estimated 180-200 cases/100,000**
**Around 600,000 New TBI occur every year**
**10% of these Injuries are fatal.**
**NIH survey estimates in USA 1.9 million  suffer skull fracture or intracranial injury, 1⁄2 have suboptimal outcome.**
**Cost  40 Billion dollars/year**

## TRAUMATIC BRAIN INJURY

## Military Fatalities:  By Time PeriodAs of 2/20/07

| Period | US | UK | Other* | Total | Avg | Days |
| --- | --- | --- | --- | --- | --- | --- |
| 5 | 998 | 34 | 21 | 1,053 | 2.43 | 434 |
| 4 | 715 | 13 | 18 | 746 | 2.35 | 318 |
| 3 | 579 | 25 | 27 | 631 | 2.92 | 216 |
| 2 | 718 | 27 | 58 | 803 | 1.89 | 424 |
| 1 | 140 | 33 | 0 | 173 | 4.02 | 43 |
| Total | 3,150 | 132 | 124 | 3,406 | 2.37 | 1,435 |

## US Non Mortal Casualties:  Including non-hostile and medical evacuations As of 2/3/07

| Non-Mortal Casualities |      Army |    Navy |   Marines |             Air Force |          Total |
| --- | --- | --- | --- | --- | --- |
| Wounded – No Medical Air Transport Required |   10,120 |        385 |           5,698 |                209 |   16,412 |
| Wounded – Medical Air Transport Required |     5,009 |         137 |           1,804 |                  55 |     7,005 |
| Non-Hostile Injuries – Medical Air Transport Required |      5,439 |        223 |              895 |                278 |      6,835 |
| Disease – Medical Air Transport Required |    16,111 |           544 |           1,209 |                840 |     18,704 |
| TOTAL – WOUNDED  | 15,129 | 522 | 7,502 | 264 | 23,417 |
| TOTAL – MEDICAL AIR TRANSPORTED |    26,559 |         904 |           3,908 |             1,173 |     32,544 |

## Traumatic Brain Injury

**Traumatic brain injury symptoms**
**      ****Inability **to find words**Inability **to perform tasks**Confabulating** (putting unrelated bits of conversation into conversation gaps)**Impulsivity****Agitation****Poor judgment **and poor insight**Sexual inappropriateness,** including a lack of sexual inhibitionsFor more information, call** (800) 877-VETS**, or visit _[www.va.gov](http://www.va.gov/)_.

## Frequency of PCS Symptoms following a MTBI

- Poor concentration	71%
- Irritability	66%
- Tired a lot more	64%
- Depression	63%
- Memory problems	59%
- Headaches	59%
- Anxiety	58%
- Trouble thinking	57%
- Dizziness	52%
- Blurry or double vision	45%
- Sensitivity to bright light	40%

- Traumatic Brain Injury, VA Health Initiative

## Causes of TBI (CDC Data)

- Transportation (MVA)  48.9%
- Falls 25.8%
- Firearms 9.7%
- Other Assaults  7.5%
- Others 7.4 %
- Unknown 0.6%

- Traumatic Brain Injury, VA Health Initiative

## Severity Grades of TBI

**Mild (Grade 1 ):** altered or LOC <30 min with normal CT or MRI, GCS 13-15, PTA < 24 hours.
**Moderate (Grade 2):** LOC < 6 hours with abnormal CT and/or MRI, GCS 9-12, PTA < 7 days.
**Severe (Grade 3 & 4):** LOC > 6 hours with abnormal CT and/or MRI, GCS < 9, PTA > 7 days.

- Traumatic Brain Injury VA Health Initiative

## Functional Correlates of Injury Pathophysiology

**Focal Cortical Contusion**: ground level fall, assault, gunshot wound. They can have Hemiparesis, aphasia, Seizures, visuoperceptual.
**Diffuse Axonal Injury:** motor vehicle accident, non-ground level fall, geriatric ground level fall. They have confuse language, amnesia, apraxia, hypoarousal.
**Hypoxic/Ischemic:** anoxia, cardiac arrest, prolonged elevated ICP. They have quadriparesis, spasticity, confusion, amnesia, hypoaraousal.

- Traumatic Brain Injury VA Health Initiative

## Frequency of PCS Symptoms following a MTBI

- Poor concentration	71%
- Irritability	66%
- Tired a lot more	64%
- Depression	63%
- Memory problems	59%
- Headaches	59%
- Anxiety	58%
- Trouble thinking	57%
- Dizziness	52%
- Blurry or double vision	45%
- Sensitivity to bright light	40%

- Traumatic Brain Injury, VA Health Initiative

## Specific or subjective PCS

**Neurological or medical**: Headaches, Dizziness/vertigo, Tinnitus, blurred or double vision, light and or noise sensitivity, Nausea and vomiting, Fatigue, sleep disturbances, Physical weakness.
**Cognitive**: Memory complaints, concentration complaints.
**Psychological**: Irritability, Increase aggression, Depression, Anxiety.

- Traumatic Brain Injury VA Health Initiative

## Referrals ( Team work)

**Audiologist**
**Kinesiotherapist**
**Neuro-ophthalmologist**
**Occupational therapist**
**Recreational therapist**
**Speech and language pathologist**
**Case manager**
**Neurologist**
**Neuropsychologist (psychologist)**
**Physiatrist**
**Psychiatrist**
**Social worker (counselor)**
**Vocational rehabilitation counselor**

- Traumatic Brain Injury VA Health Initiative

## Comprehensive Assessment of Acquired Brain Injury

-   **History:**
**    ****Accident related facts**
**    ****Initial neurological presentation**
**    ****Pre injury information**
**       ****past medical history and surgical history substance abuse**
**       ****developmental history**
**       ****educational history.**
**    ****Military and legal records**
**    ****Vocational History**
**    ****Psychological history**
**    ****Life stressors**
**    ****Family history**
**    ****Post injury treatment interventions**
**    ****Current functional status**

**Physical Examination****:**
**      ****Neurological **
**             ****Cranial nerves 1-12**
**              ****Deep tendon reflexes and pathological**
**              ****Sensory exam**
**              ****Cerebellar exam**
**              ****Motor exam**
**              ****Mental status exam**
**              ****Behavioral assessment**
**              ****Emotional/psychological status**
**      ****Musculoskeletal**
**               ****Head**
**               ****Face and temporomandibular joints**
**               ****Extremities**
**                ****Axial structures (neck, back, pelvis)**

- Traumatic Brain Injury VA Health Initiative

## Chronic cognitive problems

- Attention problems
- New learning and memory problems
- Executive control dysfunction
- Others (orientation, communication, behavioral, bradyphrenia, etc)

- Traumatic Brain Injury VA Health Initiative

## Interplay of cognitive and emotional problems

**Psychogenic/Psychiatry symptoms**
**     ****Denial**
**     ****Anger and irritability**
**     ****Depression**
**     ****Rigid compulsive/hypervigilant**
**     ****Emotional lability**
**     ****Social withdrawl**
**     ****Sense of futurelessness**
**     ****Thought disorder**
**     ****Personality and conduct disorder**

**Neurogenic symptoms**
**      ****Anasognosia (lack of awareness of impairment)**
**      ****Frustration, catastrophic reaction, reduce information**
**      ****Lack of initiative, impaired emotional expressiveness (Aprosodias), lower**
**       ****crying threshold, fatigue**
**      ****Distractability, inabilityto deal with more than one task at a time, dependence on external controls.**
**       ****Lability of emotional expressiveness (not the    underlying feeling state)**
**       ****Lack of initiative**
**       ****Impaired planning**
**       ****Aphasia, anomia, or confusion**
**       ****Impulsivity, social disinhibition**

- Traumatic Brain Injury VA Health Initiative

**Acute Pain**:”Normal sensation triggered by the nervous system to alert you to possible injury.”
**Chronic Pain**:”Pain persists, signals keep firing in the nervous system for weeks, months, even years”

- NINDS Chronic Pain information page

## Pain

- Tissue injury trigers an inflammatory cascade that will alter nociceptive function.
- Plasticity and learning play a role in pain
- Synaptic potentiation is facilitated by repetitive noxious stimulation and at the level of the brain,environmental influences alter the response to noxious stimulation.
- The brain can generate pain in the absence of input from the peripheral nociceptors or the spinal cord. e.g. phantom limb pain
- Therefore a Brain pattern generating mechanism or Neuromatrix has been proposed

- Pain: an overview, JD Loeser, R.Melzack . The Lancet 1999: 1607-1609

-    **International association for the Study of Pain**:
-   “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or describe in terms of such damage”

- JD Loeser, R Melzack, The Lancet 1999: 1607-1609 (Pain: an overview)

## Components of Pain

**Nociception**: detection of tissue damage by specialized transducers attached to A delta and C fibers. Aspirin can prevent inflammation and Local and regional anesthesia can prevent nociception.
**Perception of Pain**: triggerd by noxious stimulus, It can be generated by lesion in the peripheral or central nervous system.e.g. diabetic neuropathy, spinal cord injury or stroke. Pain can occur without nociception. The intensity of chronic pain has no relation to the extent of tissue injury or other pathology.
**Suffering**:negative response induce by pain and by fear, anxiety, stress, loss of loved objects and othr psychological states. Cassell:”Suffering occurs when the physcial and psychological integrity of the person is threatened”.
**Pain Behaviors**: results from pain and suffering and the things the person  do or does not do. Examples:”ouch”, gramacing, limping, lying down , recourse to health care, refusing to work, etc.

- JD Loeser, R. Melzack, The Lancet 1999: 1607-1609  (Pain: an overview)

|  |
| --- |

- The neurobiology of pain, Besson JM The Lancet,1999:353: 1610-1615

- Histamine, serotonin, bradykinin, prostaglandins, ATP, H+ ,NGF, TNF alpha, endothelins, interleukins

- Pain treatment options: TCA, anticonvulsants, Na+ channel blockers, NMDA receptor antagonists, opioids

## Molecular Events of PainPeripheral

**Transduction**
- TRPV1, TRPV2, TRPV3, TRPM8
- ASCI, DRASIC
- MDEG, TREK-1
- BK1, BK2
- P2K3
**Peripheral sensitization**
- NGF, TrkA
- TRPV1
- Na, 1,8
- PKA, PKC isoforms, CalMK IV
- Erk1/2, p38, JNK
- IL-1β, cPLA2, COX2, EP1, EP3, EP4
- TNFα
**Membrane excitability of primary afferents**
- Nav 1.8, Nav 1.9
- K+ channel
**Synaptic transmission *****Presynaptic***
- VGCC
- Adenosine-R
- (mGlu-R)

- J.Scholz, CJ Woolf:
- Can we conquer pain? , Nature Neuroscience 2002: 10621067

## Molecular Events of PainCentral

**Synaptic transmission *****Post*****synaptic**
- AMPA/kainate-R, NMDA-R, mGlu-R
- NK1
- Nav 1.3
- K+ channels
**Central inhibition**
- GABA, GABAA-R, GABAB-R
- Glycine-R
- NE, 5-HT
- Opioid receptors
- CB1
**Signal transduction**
- PKA, PC isoforms
- ERK, p38, JNK
**Gene expression**
- C-fos, c-jun, CREB
- DREAM

- J.Scholz, CJ Woolf: Can we conquer pain? Nature Neuroscience 2002: 1062-1067

- The National Initiative on Pain Control, 2002

- The National Initiative on Pain Control, 2002

- The National Initiative on Pain Control, 2002

- The National Initiative on Pain Control, 2002

- The National Initiative on Pain Control, 2002

- The National Initiative on Pain Control, 2002

- The National Initiative on Pain Control, 2002

- The National Initiative on Pain Control, 2002

## BRAIN IMAGING TECHNIQUES

- PET
- Requires relatively long pain stimulation periods (40 – 60s).
- Different functional states (e.g., pain and rest) are always acquired in separate scans.
- Maximum number of scans that can be acquired is limited by radioactivity dose restraints.
- Usually requires multi-patient study designs.
- Potential to map neurotransmitter systems and drug uptake in vivo and molecular imaging.
- Provides a solution in cases where fMRI cannot be accomplished because of contraindications.
- fMRI
- Offers better temporal and spatial resolution than PET.
- Pain stimuli do not need to be applied over along period.
- The control state and the active pain condition are done in the same run.
- Better suited than PET for studying cognitive effects on pain processing.
- Unlimited amount of repetitions within a single patient, allowing single participant, and follow- up studies.
- Offers less comfort to the patient (noise, body constrained in the magnet bone).
- Requires expensive fMRI-compatible stimulation and monitoring equipment.
- MEG
- Allows mapping of the sequential activation of brain structures in pain processing.
- Provides a direct measure of neuronal activity.
- The most ecological technique with the highest comfort and least distress for participants.
- Allows conclusions from single trial and single participant studies (great clinical potential).

- Brain Imaging of clinical pain states..Kipers R, Kehlet H. The Lancet Neurology 2006: 5:1033-1044

- Kupers R, Kehlet H  The Lancet Neurology 2006: 1033-1044

## 	Temporal	Spatial		Resolution	Resolution	Advantages	Disadvantages_______________________________________________________________________

- PET	>49’s	>4 mm	Measures activity and	Radioactivity.
- 			subcortical structures.	Poor temporal resolution.
- 			Stimulus-independent	Invasive technique.
- 			technique	Limited amount of scans
- 			Allows receptor binding 	possible.
- 			studies
- fMRI	100 ms – 3’s	>2 mm	Measures activity in	Poor patient comfort.
- 			cortical and structures.	Requires non-magnetic
- 			Excellent spatial 	equipment.
- 			resolution.	Stimulus-dependent
- 				technique.
- MEG	Milliseconds	>2 mm	Excellent temporal	Difficulties to measures
- 			resolution.	subcortical activity.
- 			High patient comfort.	Requires non-magnetic
- 			Ecological method.	equipment.
- 				Stimulus-dependent technique.
- ____________________________________________________________________________________
-            Characteristics of different brain imaging techniques used in the study of pain.

- Kupers R, Kehlet H  The Lancet Neurology 2006:1033-1044

- Kupers R, Kehlet H, The Lancet Neurology 2006:1033-1044

## METHODOLOGICAL DIFFICULTIES IN DESIGN OF BRAIN-IMAGING STUDIES IN CHRONONIC PAIN

- Difficulty in finding a homogeneous population of chronic-pain patients.
- Difficulty in discerning pain-related from psychological-related effects.
- Possible confound by differences in genetic constitution.
- Difficulty in dissociation of deafferentiation-related from pain-related changes in brain activation patterns.
- Homologous contralateral area is not an unbiased site fro non-painful control stimulation.
- Difficulty in switching pain on and off in a very precise and time-locked manner.
- Effects of therapeutic interventions could be difficult to dissociate from pain-related effects.

- Kupers R, Kehlet H.The Lancet Neurology 2006:1033-1044

- B.R. Buchbinder, Division of Neuroradiology MGH, Boston, MA

- B.R.Buchbinder, Division of Neuroradiology MGH, Boston, MA

- Emergency Neuroradiology, M.Rothman et al. e-medicine, Oct 29, 2003

**Epidural Hematoma**

- Head Injury, Olson DA et al. e-Medicine Oct 2, 2006

**Right subdural hematoma**

**Intraparenchymal bleeding**

- Head Injury, Olson DA et al. e-Medicine Oct 2, 2006

**Left frontal contusion**

**Right linear contusion**

- Emergency Neuroradiology, M Rothman, e-medicine Oct 29, 2003

**Bullet**

- Emergency Neuroradiology, M.Rothman, e-medicine Oct 29, 2003

**Metallic rod**