+2 Frontal Lobe

Again, we found that the patients without psychiatric comorbidity were the ones with the highest number of abnormalities—usually small, circumscribed areas of T2 signal in frontal lobes <a href="https://www.frontiersin.org/articles/10.3389/fphys.2013.00109/full">Frontiers | Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration | Physiology</a>

Symptoms of Frontal Lobe Disorders:

Mood Disruption – Personality Changes – Paralysis – Sequencing – Perseveration – Inability to focus on a task

The Frontal Lobes and
Traumatic Brain Injury
Marilyn F. Kraus, M.D., Harvey S. Levin, Ph.D.
The involvement of the frontal lobes in closed head
injury (CHI) is supported by both neuropathological
and neuroimaging studies that show that this region is
the most common site of focal brain lesions.

NEUROPSYCHIATRIC SEQUELAE
OF CLOSED HEAD INJURY
Although the frontal and temporal lobes are commonly
involved, CHI can cause a heterogeneous group of
neuropsychiatric symptoms because the injuries tend
to be diffuse, rarely limited to one discrete brain region
or functional system. Dysfunction can occur in
aspects of cognition, mood, and behavior. A rather
loosely defined diagnosis of postconcussional syndrome
is often used, although it is not well qualified or
quantified. Features can include headache, dizziness,
fatigue, disrupted sleep, restlessness, photophobia
and phonophobia, mood disturbances, disorganized
thinking, apathy, disinhibition/impulsivity, memory
impairment, and attention/concentration deficits. Seizures
can follow different severities of CHI and most
commonly are partial complex. This also adds to the
risk of neuropsychiatric sequelae. Although relatively
uncommon, and usually seen only with more severe
injuries, psychotic symptoms can occur or even develop
over time. CHI of different severities may result in
any combination and quality of these symptoms. Generally,
the symptoms of postconcussional syndrome
are self-limited in mild, uncomplicated injuries, as
shown in a multicenter trial.30 But a subgroup of patients
with mild CHI continue to have persistent deficits.
Many have difficulty returning to work, home, or
school after CHI. For all severities of injury, providing
a comprehensive evaluation that addresses the patient’s
deficits and educates the family about the sequelae
of CHI is essential to developing an effective
treatment plan.
In many cases, frontal lobe dysfunction contributes
to a broad range of symptoms and deficits.31 Clinicians
should become familiar with the signs and
symptoms of the various disorders of mood, behavior,
and cognition, such as the prefrontal syndromes, that
can be seen after CHI. Appreciating the neurological
antecedent to these sequelae is important so that treatment
is appropriate and rational. The prefrontal syndromes
have been reviewed in detail elsewhere32,33
and in Chapters 3 and 8 in this book. In the remainder
of this chapter, we provide an overview of common
problems and pharmacological treatment options.
Mood disturbance is common after CHI.34,35 True
depression or mania may develop, but mood lability is
probably the most frequent mood-related complaint
after CHI. Robinson et al.36 and others37 have reported
that mood disturbance may be lateralized following
CHI, with mania more common after right frontal injury
and depression more likely to follow left frontal
trauma. Family members often report that patients
have lost their ambition or, alternatively, that they
seem “wired” and cannot control their behavior. Differentiating
depression from apathy and hypomania
from disinhibition (both common in prefrontal dysfunction)
may be difficult in some patients. If neuropsychological
evaluation and knowledge of the pathology
point to prefrontal dysfunction, it is rational
to direct treatment accordingly.
Cognitive problems following CHI range from decreased
attention and concentration to prominent amnesia
and disorganized thinking. Some patients appear
to have developed attention-deficit disorder;
they may become easily distracted and restless and
may feel overstimulated. Restlessness and difficulty in
processing multiple stimuli are often significant problems.
Mentation may slow down, and cognitive flexibility
may decrease. The ability to carry out activities
that require sequencing and multiple steps may become
impaired. Diminished insight can cause patientsto insist on returning to their preinjury responsibilities
despite their new cognitive limitations. In more advanced
cases, cognitive dysfunction may cause patients
to rely on others to oversee their activities of daily
living (see Salloway, Chapter 10, “Case 6: Traumatic
Brain Injury,” in this volume).
The difficulty that many CHI patients experience in
adapting to novel environments may lead to repeated
failures in new and challenging work settings. These
failures, when seen in conjunction with apathy (associated
with mesial frontal pathology), are often interpreted
as indicative of a personality disorder.
Dyscontrol syndromes may predominate when the
injury involves the orbitofrontal surface of the frontal
lobes.38 Patients with these syndromes may appear
jocular, impulsive, shallow, and insensitive and can
lose the capacity to monitor and regulate their behavior.
Milder cases may be limited to increased irritability,
a “short fuse,” and verbal hostility toward friends
or family. At the more extreme end, physical violence,
impulsive self-destructive behavior, or sexual disinhibition
may be apparent. These patients may meet criteria
for antisocial personality disorder and have been
called “pseudopsychopathic.”38 Clinically, traumatically
brain injured patients tend to have diffuse injury
to the prefrontal cortex, with resulting variability in
deficits and symptoms.
Milder CHIs can magnify preexisting negative personality
traits.39 At the other extreme, caregivers may
hardly recognize the patient’s personality. The patient
may alienate family members at a time when support
is critical. The patient may try to return to work, only
to find the workplace overwhelming and distracting.
40 Conflicts may develop with co-workers and superiors.
The patient may use loud and inappropriate
language to express frustration. The loss of productivity
and decrease in occupational and family status can
have a highly negative effect on the patient’s selfesteem.
PHARMACOLOGICAL TREATMENT
Historically, pharmacological intervention with braininjured
patients has been based chiefly on experience
involving primary psychiatric disorders, developmental
disorders, and clinical experience. Treatment
can be aimed at observable symptoms, based on
hypotheses about the underlying neurochemical dysfunction,
or both. To date, there have been few published
reports of controlled trials.41 Only a brief overoverview
of current pharmacological interventions is
presented here; the reader is referred to the listed references
for more detail.
With frontal pathology, mood dysregulation is
common, ranging from depression to lability. Antidepressant
medications, carbamazepine, or sodium valproate
may help to stabilize mood after CHI.42 The anticonvulsants
carbamazepine and valproate, as well as
the newer agents such as gabapentin, can be useful not
only for mood stabilization but also for irritability and
aggression. Gabapentin is showing promise as a treatment
for chronic pain, and we have found it very useful
for chronic headaches following CHI.43 Choice of
agent, dosage, and side effects should be carefully
monitored because patients with CHI tend to be more
sensitive to psychoactive agents than are patients with
primary mood disorders. The serotonergic antidepressants
are often well tolerated and effective. In the setting
of frontal lobe dysfunction, dopaminergic agents
such as amantadine or levodopa/carbidopa can stabilize
mood.44,45
Treatment of cognitive dysfunction begins with
modifying the patient’s environment to prevent overstimulation.
Structure and routine are especially important
when the frontal lobes are impaired. Clinical
evidence, primarily from case reports, indicates that
certain cognitive deficits can improve with pharmacological
interventions. Case reports and small case series
support the use of the psychostimulants in patients
with head injury.46–50 Methylphenidate and
dextroamphetamine enhance dopaminergic and noradrenergic
transmission,51 which may partly explain
their effectiveness. Many of the symptoms experienced
by these patients resemble those of attentiondeficit
disorder, so these agents represent a logical
choice. They are often very effective for symptoms of
distractibility, impaired attention span, impulsivity,
and irritability. They also can be useful for organic
mood disorders such as depression in medically or
neurologically ill patients, and they are very well tolerated
in the dosages used.52–56 Clinically, negative effects
on seizure threshold are not common. Animal
studies suggest that these agents can be beneficial in
enhancing cortical recovery.57 Controlled studies are
under way in human subjects, and a preliminary report
by Plenger et al.58 is encouraging.
Dopaminergic agents such as amantadine, levodopa/
carbidopa, and bromocriptine also have shown
clinical usefulness in patients with head injury.44,45,59,60
Anderson et al.61 described positive results on visual
attention, speed of information processing, attentionspan, learning capacity, and alertness in two patients
with traumatic brain injury who were given amantadine,
200–400 mg/day. Amantadine has been used in
other populations, such as in Alzheimer’s dementia
patients, for a variety of symptoms. A controlled
study in which amantadine was used for mild dementia
found augmented P300 amplitude, suggesting improved
cognitive processing.62 Apathetic or disinhibited
and impulsive patients may respond to treatment
with dopamine agonists with minimal side effects. In
a published case series, Kraus and Maki44 assessed
the effectiveness of amantadine hydrochloride. It improved
several measures of cognitive function significantly
and behavior problems associated with frontal
lobe dysfunction, such as apathy, impulsivity, and disinhibition,
in a series of seven patients whose original
injury occurred at least several years earlier. Following
up on these preliminary clinical data, Kraus et al.63 reported
on an open trial of amantadine hydrochloride
in 23 subjects with traumatic brain injury that had occurred
at least 6 months ago. Significant improvement
was found for several tasks representing frontal lobe
function, attention, and motor speed. On clinical assessment,
11 subjects reported improvement in all
three areas assessed—cognition, mood, and behavior.
Nine reported improvement in only one or two areas;
three denied any response, although one subject
showed areas of improvement on repeat testing.
Clinically, in our experience, the addition of a second
dopaminergic agent such as levodopa/carbidopa
may enhance response but needs to be done carefully
because of increased risk of side effects.45 Not all patients
improve, however, and side effects such as increased
agitation, gastrointestinal symptoms, decreased
appetite, and, rarely, psychosis may occur.42
An agent originally developed for Alzheimer’s dementia
is showing promise as a cognitive treatment
for traumatic brain injury. We have used the cholinesterase
inhibitor donepezil with some success in improving
memory and cognition in some of our patients,
often in combination with other treatments
such as a dopaminergic agent. At present, only case reports
are available,64 and larger controlled studies
must be done.
In the first published pilot report on the use of
amantadine in recovery from experimental traumatic
brain injury, Dixon et al.65 assessed the effect of daily
amantadine treatment on functional recovery (motor
and spatial memory performance) following traumatic
brain injury in rats based on a controlled cortical impact
model. Amantadine-treated rats improved significantly
during a 5-day water maze task. Daily administration
of amantadine significantly enhanced
recovery of spatial memory performance deficits but
not motor deficits following traumatic brain injury. Investigation
is under way to assess this potential effect
on recovery in traumatic brain injury patients.
The efficacy of amantadine in traumatic brain injury
may be attributable to its effect on dopamine transmission,
its role as an N-methyl-D-aspartate antagonist, its
effects on the balance among different neurotransmitter
systems, or a combination of these attributes.
In general, anticholinergic agents should be avoided,
if at all possible, because of the potential for aggravating
cognitive deficits and for lowering the seizure
threshold in brain-injured patients. Neuroleptics
should be reserved to use as a treatment of last resort.
They not only can aggravate symptomatology but also
may be deleterious to cortical recovery.57
Treatment of frontal lobe dysfunction can be difficult.
Along with a good psychosocial assessment, information
about alcohol and drug use should be obtained
because substance abuse may exacerbate
problems of self-control. In addition to the dopaminergic
agents, the selective serotonin reuptake inhibitors,
buspirone, trazodone, β-adrenergic receptor
blockers, and anticonvulsant medications have been
used to treat aggression, disinhibition, and dyscontrol.
59,66 Prescribing multiple medications is often unavoidable.
For example, our experience suggests that
combining dopaminergics with serotonergic agents
(e.g., sertraline) or carbamazepine can have an additive
or possibly a synergistic effect in brain-injured patients
with a range of symptoms and deficits. Obviously,
more controlled studies are needed.
Nonspecific symptoms, such as headache and sleep
disturbance, also are common following injury. Alone,
these symptoms can affect mood and cognition adversely.
Following CHI, they can significantly interfere
with recovery and rehabilitation. These symptoms
are sometimes self-limited or may respond
secondarily to treatment aimed at other symptoms,
such as mood disorders.
Posttraumatic headache has not been well studied
but tends to have a mixed tension-vascular quality.
Stress, overstimulation, and exposure to noise and
bright light bring on a headache for many patients.
The treatment of posttraumatic headache is essentially
the treatment of chronic headache. Current guidelines
for the treatment of migraine or tension headache can
be used.67 However, caution should be used to avoid
agents, such as anticholinergics or narcotics, thatcould be problematic in head-injured patients. Current
wisdom cautions against the chronic use of nonsteroidal
anti-inflammatory drugs, which can actually
worsen the problem.68 Instead, long-term prophylaxis
with agents such as antidepressants, calcium channel
blockers, valproate, or β-blockers can be instituted.67
The serotonergic antidepressants, including fluoxetine
and sertraline, may be useful. If anticholinergic
side effects develop with use of low-dose amitriptyline,
nortriptyline may be a more reasonable choice.
Sleep disturbances also aggravate other symptoms
and interfere with recovery. Again, care should be taken
in choosing pharmacological treatment. Often,
headache and sleep disturbance occur together; in this
case, we find that nortriptyline can be very helpful if
tolerated. A low dose of trazodone also can be effective,
along with education about sleep hygiene. A regular
schedule is important because disrupted sleepwake
cycles are common and aggravate other symptomatology.
CONCLUSIONS
The frontal lobes are frequently involved in CHI. Although
injury to the brain is often diffuse, specific cognitive,
behavioral, and mood disorders can reasonably
be attributed to frontal lobe damage, directly or indirectly.
Treatment and rehabilitation require a multidisciplinary
approach. Educating the patient and family
about the sequelae of CHI is essential. Modifying the
patient’s home and work environments often leads to
a significant improvement in the patient’s level of
functioning. Pharmacological interventions can be effective
in certain cases and can enhance rehabilitation
efforts.

VULNERABILITY OF THE FRONTAL
LOBES TO CLOSED HEAD INJURY
Pathophysiology and Neuroimaging Evidence
The proximity of the orbitofrontal and anterior temporal
regions to bony protrusions and cavities contributes
to their vulnerability to injury, particularly when
rotational acceleration is imparted to the freely moving
head.1 Acceleration-deceleration forces can cause
the brain to be forced up against these bony surfaces,
causing both coup and contrecoup injury. Of the
mechanisms of diffuse injury in CHI, diffuse axonal
injury is of particular significance because it produces
profound shearing and stretching of axons throughout

the brain and brain stem, as well as focal lesions in the
corpus callosum.2 This white matter damage can be
diffuse and may not be detectable on structural imaging.
Perhaps the most unequivocal evidence for the
vulnerability of the frontal lobes after CHI was obtained
in Glasgow by J.H. Adams and his co-workers,1
who developed a contusion index based on the size
and depth of contusions in fatal injuries. Adams et al.
found that the contusion index was greatest in the
frontal lobes, followed closely by the anterior temporal
region.
Neuroimaging studies have extended the findings
of frontal lobe vulnerability to less severe CHI. In a
magnetic resonance imaging (MRI) study of mild to
moderate head injuries, Levin et al.3 reported the results
of serially scanning 50 consecutive admissions.
As shown in Figure 14–1, the frontal lobes were the
most common site of focal lesion, that is, abnormal signal
on MRI. Figure 14–2 depicts the resolution of abnormal
signal over the first 1–3 months after mild to

moderate CHI, which was paralleled by recovery of
neurobehavioral functioning.
The issue also arises of apparent frontal lobe injury
that, although it is suggested by the biomechanics of
the injury, neuropsychological testing, and neurobehavioral
disorder, eludes currently available structural
neuroimaging.4 Preliminary evidence suggests that
the substrate of deficits that clinicians and investigators
attribute to frontal lobe dysfunction in headinjured
patients could be elucidated by functional imaging.
5,6
Neuropsychological Evidence
The vulnerability of the frontal lobes to damage in
CHI has been invoked to explain the frequent disruption
of executive control functions involving mood,
behavior, and aspects of cognition.7 The functional
heterogeneity of the orbitofrontal and dorsolateral regions
has received support from experimental investigation
of nonhuman primates8 and case reports of patients
with focal frontal lesions.7 Goldman8 showed a
dissociation between the effects of dorsolateral and orbitofrontal
lesions on delayed response performance
in monkeys; this dissociation depended on their age at
the time of ablation and when they were tested. Thus,

the clinical picture in frontal lobe damage is variable
and depends on several factors, including not only the
characteristics of the injury itself but also the premorbid
functioning and age of the individual.
Clinical descriptions of patients who have sustained
severe head injury often include features that
are associated with frontal lobe injury, such as poor
impulse control, decreased flexibility, impaired attention,
perseveration, and diminished divergent thinking,
particularly on measures of verbal fluency and
figural fluency. Often, however, these neurobehavioral
features demonstrated on testing are not associated
with firm evidence of frontal lobe damage from structural
brain imaging. The neuropsychological evidence
for frontal lobe dysfunction after CHI is derived from
several studies, including the work by Stuss and colleagues.
The study reported by Stuss et al.4 in 1985
was quite provocative because it included patients
who were thought to have attained a good recovery
yet showed impairments on tasks that are widely used
to assess frontal lobe functions, such as interference
effects on the Stroop Test, difficulties with attention,
and vulnerability to interference on memory tests.
Stuss et al. found that patients who had relatively preserved
performance on the Wechsler Adult Intelli-

gence Scale (WAIS) nevertheless had difficulty with
shifting and maintaining responses on the Wisconsin
Card Sorting Test (WCST). The study by Stuss et al.
matched a healthy control group (on age, education,
and the WAIS) with the survivors of head injuries who
were thought to have attained a good recovery. Stuss
et al. found that the head-injured patients showed an
impairment on interference memory tests, that is, on
the Brown-Peterson task, in which a series of three
consonants or vowels is presented and the patient is
then asked to count backward as an interference test.
After a variable delay, the patient is asked to recall the
three syllables. Stuss et al. found that the CHI patients
had difficulty in recalling the series of letters after a
delay filled by the distractor interference task. Taken
together, the pattern of neuropsychological findings reported
by Stuss et al. implicated frontal lobe dysfunction.
However, this study lacked neuroimaging to provide
clinicopathological correlation with the cognitive
testing.
NEUROBEHAVIORAL SEQUELAE
OF FRONTAL LOBE INJURY IN
ADULTS AND CHILDREN
Current evidence indicates that although maturation
of the frontal lobes extends at least into adolescence,
9,10 developmental changes in performance on a

task similar to delayed response have been documented
even in human infants.11 In adults who experience
a CHI involving the frontal lobes, already established
functions are disrupted. An understanding of the
component parts of this so-called syndrome can allow
for more effective evaluation and intervention. Case
reports of frontal lobe injury sustained during childhood
and during adulthood have documented the development
of cognitive deficit and aberrant behavior,
as illustrated below.
Early Frontal Lobe Injury
Price et al.12 described a young woman who was referred
for evaluation because of alleged child neglect.
History revealed that at age 4, Ms. A had sustained
a head injury when she was struck by a car.
An MRI scan showed bilateral frontal lobe damage
that involved the right hemisphere to a greater extent
than the left. Neuropsychological assessment
disclosed a low normal intellectual level (WAIS
Verbal IQ=78; Performance IQ=83). The patient
showed a marked susceptibility to interference on
the Stroop Interference Task, in which one has to
overcome the dominant tendency to read the
names of color words rather than to specify the color
of the print in which the word appears. In addition,
Ms. A had difficulty in performing Trail Making
B, in which she was asked to alternate between
numeric and alphabetic sequences. What was even
more striking about this patient than her cognitive
deficits was that she showed very poor judgment
and also, over the years following her injury,