Thalamic integrity underlies executive dysfunction in traumatic brain injury.

OBJECTIVE: To quantify the effects of traumatic brain injury on integrity of thalamocortical projection fibers and to evaluate whether damage to these fibers accounts for impairments in executive function in chronic traumatic brain injury. METHODS: High-resolution (voxel size: 0.78 mm x 0.78 mm x 3 mm(3)) diffusion tensor MRI of the thalamus was conducted on 24 patients with a history of single, closed-head traumatic brain injury (TBI) (12 each of mild TBI and moderate to severe TBI) and 12 age- and education-matched controls. Detailed neuropsychological testing with an emphasis on executive function was also conducted. Fractional anisotropy was extracted from 12 regions of interest in cortical and corpus callosum structures and 7 subcortical regions of interest (anterior, ventral anterior, ventral lateral, dorsomedial, ventral posterior lateral, ventral posterior medial, and pulvinar thalamic nuclei). RESULTS: Relative to controls, patients with a history of brain injury showed reductions in fractional anisotropy in both the anterior and posterior corona radiata, forceps major, the body of the corpus callosum, and fibers identified from seed voxels in the anterior and ventral anterior thalamic nuclei. Fractional anisotropy from cortico-cortico and corpus callosum regions of interest did not account for significant variance in neuropsychological function. However, fractional anisotropy from the thalamic seed voxels did account for variance in executive function, attention, and memory. CONCLUSIONS: The data provide preliminary evidence that traumatic brain injury and resulting diffuse axonal injury results in damage to the thalamic projection fibers and is of clinical relevance to cognition.

Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET).

PRIMARY OBJECTIVE: This study was performed to assess effects of amantadine (AMH), a dopaminergic agent and NMDA antagonist, on chronic traumatic brain injury (TBI). The primary hypotheses were that amantadine treatment would result in executive function improvement and increased activity in pre-frontal cortex. RESEARCH DESIGN: An open-label design was used. METHODS: Twenty-two subjects underwent neuropsychological testing pre- and post-12 week treatment. Six subjects also underwent PET scanning. INTERVENTION: Amantadine 400 mg was administered per day. RESULTS: Significant improvements on tests of executive function were observed with treatment. Analysis of PET data demonstrated a significant increase in left pre-frontal cortex glucose metabolism. There was a significant positive correlation between executive domain scores and left pre-frontal glucose metabolism. CONCLUSIONS: This is the first known study to assess amantadine in chronic TBI using PET and the data are consistent with the hypotheses. The conduction of further studies is warranted.

The combined use of amantadine and l-dopa/carbidopa in the treatment of chronic brain injury.

The frontal lobes are particularly vulnerable to injury during trauma. The syndrome commonly attributed to frontal lobe dysfunction includes problems with impulsivity, perseveration, disinhibition, amotivation, attention, planning, and problem solving. These symptoms can respond to certain pharmacologic interventions, such as the dopaminergic agents. The case of a 50-year-old woman who showed persistent frontal dysfunction 5 years post-injury is described. After treatment with amantadine alone, she showed decreased impulsivity and perseveration and improved executive function. Further positive response was obtained with the addition of l-dopa/carbidopa, with additional improvements in constructional praxis, divided auditory attention, and cognitive flexibility. Her improved functioning following treatment demonstrates the potential for increasing effectiveness through a combination of dopaminergic agents. No side effects were observed, and the patient maintained gains at follow-up. The rationale for using dopaminergic agents alone and in combination is discussed.

Effect of amantadine hydrochloride on symptoms of frontal lobe dysfunction in brain injury: case studies and review.

Symptoms consistent with dysfunction of the frontal lobes can occur following traumatic brain injury (TBI) or other types of acquired brain injury (stroke, aneurysm). These symptoms can include problems with short-term memory, attention, planning, problem solving, impulsivity, disinhibition, poor motivation, and other behavioral and cognitive deficits ("frontal lobe syndrome"). These symptoms may respond to certain drugs, such as dopaminergic agents. This case series describes results of using amantadine in 7 patients with this type of symptom profile (6 with TBI, 1 with meningitis following sinus surgery). Patients received neuropsychiatric examinations and serial neuropsychological testing. All patients showed some degree of positive response. One had side effects that resolved upon discontinuation of drug. The rationale for using dopaminergics is discussed, and pertinent literature is reviewed.

Guidelines for the use of tacrine in Alzheimer's disease: clinical application and effectiveness. Johns Hopkins Dementia Research Clinic.

The efficacy of tacrine for treatment of Alzheimer's has been demonstrated in several clinical trials but has not been assessed in cases complicated by medical and psychiatric comorbidities. Additionally, the benefit-risk ratio of tacrine is small, so it is best administered with carefully developed guidelines that specify this ratio for patients and families. On the basis of guidelines developed for the Johns Hopkins Dementia Research Clinic, tacrine treatment was offered to 162 patients with probable Alzheimer's. Only 35 accepted, and only 22 continued on tacrine beyond 3 months. The latter group declined by 1.36 points over 1 year on the Mini-Mental State Examination, significantly less than expected. The authors conclude that, if used in the context of clinical guidelines, tacrine is an effective treatment for Alzheimer's.

Neuropsychiatric sequelae of stroke and traumatic brain injury: the role of psychostimulants.

OBJECTIVE: The primary purpose of this article is to review certain neuropsychiatric sequelae of stroke and traumatic brain injury (TBI), and the role of the psychostimulants methylphenidate (MPD) and dextroamphetamine (DAMP) in their treatment. METHOD: A general review of the topic is presented. Controlled and uncontrolled studies involving the use of the psychostimulants are discussed. These consist of 11 studies listed with Medline 2000 that deal specifically with stroke or head injury, with the oldest study reviewed dating back to 1984. Studies concerning the use of psychostimulants in the medically or neurologically ill are reviewed to the extent that they are pertinent. RESULTS: The current literature consists primarily of uncontrolled case studies. However, these are reviewed and found to suggest a role for the use of the psychostimulants, which is discussed. CONCLUSIONS: In general, these drugs appear to be a reasonable treatment choice for certain types of mood, behavior, and cognitive symptoms following brain injury. However, it is noted that larger scale controlled studies are needed to adequately assess the clinical usefulness of these drugs.

The frontal lobes and traumatic brain injury.

The authors review 1) the pathophysiological, neuroimaging, and neurobehavioral evidence for frontal lobe involvement in closed head injury; 2) studies elucidating the cognitive deficits and behavioral disturbance related to frontal lobe lesions associated with head injury; and 3) pharmacologic treatment of the neuropsychiatric manifestations of frontal lobe injury, including emerging therapies.

Methylphenidate hydrochloride as an antidepressant: controversy, case studies, and review.

The use of psychostimulants as antidepressants remains controversial in the field of psychiatry. While methylphenidate hydrochloride (MPH) and dextroamphetamine (DA) are often considered to be equivalent drugs, differences in their neurobiologic mechanism of action may account for different clinical response patterns. Hence, clinical trials and literature reviews that examine the antidepressant efficacy of psychostimulants without distinguishing between MPH and DA may reach inaccurate conclusions. This paper is a critical review of controlled and uncontrolled studies examining the use of MPH as an antidepressant. We discuss the methodologic limitations of existing placebo-controlled trials that have reached mixed conclusions about the efficacy of MPH as an antidepressant. These studies are offset by uncontrolled open trials and clinical case reports that endorse the drug's effectiveness in alleviating depressive symptoms. The series of patients we treated with MPH demonstrates the safety and efficacy of this drug in alleviating depressive symptoms in the medically ill elderly with a variety of mood disorders. Reviewing these six cases and balancing the positive and negative reports in the literature, we provide practical guidelines for identifying patients who are potential candidates for treatment with MPH.