Functional deficits

The proposal that NO or its reactant products mediate toxicity in the brain remains controversial in part because of the use of non-selective agents such as those listed above that block NO formation in neuronal, glial, and vascular compartments. Nevertheless, a major area of research has been into the potential role of NO in neuronal excitotoxicity. Functional deficits following cerebral ischaemia are consistently reduced by blockers of NOS and in mutant mice deficient in NOS activity, infarct volumes were significantly smaller one to three days after cerebral artery occlusion, and the neurological deficits were less than those in normal mice. Changes in blood flow or vascular anatomy did not account for these differences. By contrast, infarct size in the mutant became larger... 

Drawing all this evidence together, Schildkraut (1965) concluded that depression was caused by a functional deficit of noradrenergic transmission in the brain. He also thought that the rebound depression and fatigue, which are experienced after the arousing effects of amphetamine have worn off, were due to depletion of neuronal stores of noradrenaline. However, Schildkraut made a clear distinction between the effects of antidepressants and the arousal induced by amphetamine, describing the latter as stimulation and excitement . To this day, there is controversy over whether or not amphetamine has a beneficial effect in depression. 

Functional Deficits Resulting from Amphetamine Neurotoxicity... 

Rats that have lost dopamine and/or serotonin terminals following treatment with amphetamine, methamphetamine, MDMA, MDA, / -chloroamphetamine, or fenfluramine show little in the way of overt ehanges in appearanee or behavior. Dr. Rieaurte (this volume) emphasized the need for more studies in primates, since MPTP-treated miee also show little in the way of observable functional changes, whereas MPTP-treated monkeys show marked neurologie deficits. It may be neeessary to do more detailed analysis of speeifie behaviors and other funetional outputs that are influeneed by dopamine and/or serotonin neurons, to detect functional deficits induced by some neurotoxic drugs. For instance, specific behaviors sueh as appetite-eontrolled behavior (Leibowitz and Shor-Posner 1986), murieidal behavior (Katz 1980), and sexual behavior (Tucker and File 1983) elieited by drugs... 

Abeliovich, A. et al. Mice lacking a-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25 239-252,2000. 

Within 30 minutes of their administration, 6 -adrenergic drugs often reverse most of the functional deficit in Monday morning byssinotics. As there is no mucous secretion, airway smooth muscle contraction is considered the primary response. Exposure of man to histamine aerosols produces pulmonary function changes similar to those seen after exposure to dust extract. However, exposure to histamine aerosol invariably initiates constriction of smooth muscle more rapidly than exposure to cotton dust ( <15 minutes), and dissipates within minutes, while the acute effects of inhalation of cotton dust and dust extracts lasts for hours. The slowly developing and prolonged effects of dust and extracts suggest that mediators other than histamine are involved. 

Among the aged, deficiency of vitamin B12 is rather common. Upon aging, many people become unable to absorb adequate amounts of vitamin B12 from the diet. Functional deficits are the result. These are easily overcome by the monthly injection of vitamin B12 supplements. 

Loss or mutation that inactivates one copy of the gene can be tolerated because there is no functional deficit in the heterozygous condition. 

The four major categories of manifestations of altered development are death, malformation, growth retardation, and functional deficits. 

There are a number of useful standardized scales to monitor severity and treatment outcomes, (reviewed by Conners [1998] and Barkley [1998]) Because of the overlap with other disorders, an ADHD-specific scale is strongly recommended (such as the Conners, SNAP, Dupaul scales) in which symptom items are based on the DSM criteria and do not include items of other disorders (such as anxiety or mood) or nonspecific functional items. Some ADHD scales provide separate ratings of oppositionality or aggression (SNAP, Conners). It may be helpful to monitor symptoms from non-ADHD conditions as well as functional deficits, and thus a broad-spectrum scale may also be employed but should not be used as the primary measure of ADHD severity or anti-ADHD treatment. Normed rating scales provide comparative information on severity based on age and gender however, such tests are not diagnostic and are not a substitute for the clinical interview. 

If the functional deficit in AD is the result of neuronal and synapse loss, the ideal strategy would be to use techniques to reestablish neuronal and synaptic viability. In this sense, trophic factors are very promising. The positive results obtained in animal models of AD with brain tissue implantations with NGF and the memory enhancement and learning from laboratory animals treated with NGF have opened new windows to the possibility of the clinical use of NGF to treat AD. However, the potential benefits of the NGF may be counterbalanced by its capacity to increase the P-APP synthesis, consequently having an adverse effect in the progression of the illness. The increase of the APP synthesis may not necessarily affect all APP isoforms equally. The possibility of aberrant synapses and of alterations in the metabolism of the t- and P-amyloid protein exists [F. Hefti et al. 1995). 

Stoll AL, Locke CA, Vuckovic A, et al. Lithium-associated cognitive and functional deficits reduced by a switch to divalproex sodium a case series. J Clin Psychiatry 1996 57 356-359. 

Zhang, R., Zhang, L., Zhang, Z., Wang, Y., Lu, M., Lapointe, M., Chopp, M. (2001). A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol, 50, 602-11. 

Cellular therapy is the replacement of lost or dysfunctional tissues with new ones. Various cell types have been evaluated and considered for therapy. In the CNS, fetal neuronal tissue has been particularly evaluated for its merit in treating neurological diseases and injuries [1]. While numerous experimental and clinical transplantation studies showed that fetal neuronal transplants improve functional deficits in models of CNS diseases [2-5], others reported less positive outcomes [6, 7]. In addition, the rate of survival of fetal neuronal cells transplanted into the adult brain is relatively low, requiring large quantities of tissue, generally from several fetuses, for therapy. Researchers are looking at other opportunities for cellular therapy, particularly in the CNS. 

In another report describing the same cohort of workers as studied by Rosenman et al. (1979), Moss et al. (1979) conducted electrophysiological and psychophysiological studies of the eyes of 7 of the 10 workers who had complained of decreased night vision. No functional deficits were found in the vision of these workers. 

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