Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteers.

OBJECTIVE: To assess the bioequivalence of two fluoxetine hydrochloride capsule (20 mg) formulations (Fluoxicare capsule from Pharmacare Ltd., Chemicals and Cosmetics, Ramallah, Palestine, as test formulation, and Prozac from Eli Lilly Ltd., Basingstoke, UK, as reference formulation). DESIGN AND METHODS: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period. Participants were 24 healthy male volunteers aged 18-28 years, divided into 2 groups of 12 subjects. One group was given the originator drug (reference formulation), and the other was given the test formulation. Blood samples were obtained at baseline and at 14 time points during the interval 0-96 hours after drug administration. The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer. We calculated the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and time of maximum plasma concentration (tmax) for each subject. Logarithmic transformation of the AUC and Cmax was used for the statistical analyses and to assess the bioavailability of the two formulations, using analyses of variance (ANOVA) and Satherwait t-tests for unequal variances. The ANOVA performed of tmax in Cmax, and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90% confidence intervals for the differences between study variables after administration of the test and reference formulations. Statistical analyses were conducted on AUC 0-4 as the extrapolated part of the AUC, a truncated area approach was adapted. RESULTS: The mean pharmacokinetic parameters for both of the drugs under study were as follows: Cmax = 61.24 (+/- 12.96) ng/ml for the test formulation, and for the reference formulation Cmax = 61.39 (+/- 14.1) ng/ml, the effects were statistically equivalent. The tmax for the test formulation was 8.25 (+/- 1.7) and 7.33 (+/- 0.96) for the reference formulation. The area under the curve to infinity (AUC 0-infinity (ng, day/ml)) for the test formulation and for the reference formulation were 293.02 (+/- 52.69) and 296.15 (+/- 61.69), respectively. CONCLUSIONS: The two formulations had equivalent pharmacokinetic parameters, were well-tolerated, and their relative bioavailability was 98.94%.

Selective delayed response deficits in Parkinson's and Alzheimer's disease.

Experimental paradigms adopted from animal models were used to contrast the functional anatomy of frontal systems involved in Alzheimer's disease and the dementia of Parkinson's disease. Patients with Parkinson's disease with dementia were compared with patients with Alzheimer's disease, and nondemented patients with Parkinson's disease, and normal controls. The tasks administered, delayed alternation and delayed response (DR), are sensitive to frontal system damage. Different aspects of each task are mediated by separate frontosubcortical neuronal networks. Patients with Parkinson's disease with dementia were significantly impaired only on DR, whereas patients with Alzheimer's disease were impaired on DR and delayed alternation, even though both groups were equated for severity of dementia. Although dysfunction in the frontal lobes, and/or their subcortical connections, is implicated in both Parkinson's and Alzheimer's disease, dorsolateral frontal systems appear primarily impaired in Parkinson's disease, whereas dorsolateral frontal impairment combined with other regions, possibly orbitofrontal, are prominent in Alzheimer's disease.

Tactile discrimination learning deficits in Alzheimer's and Parkinson's diseases.

Neuropsychological mechanisms of dementia in Alzheimer's and Parkinson's diseases were compared using a tactile discrimination learning paradigm adopted from animal models. There were two components to the task: tactile original learning (TOL), which is sensitive to parietal lobe damage in nonhuman primates; and tactile reversal of original learning (TRL), a measure of perseveration. The patients with Alzheimer's disease were significantly impaired on TOL compared with demented patients with Parkinson's disease, even though both groups were equated for severity of dementia. On TRL, the patients with Alzheimer's disease and demented patients with Parkinson's disease were both significantly impaired, but the patients with Alzheimer's disease showed significantly more perseverative errors. The mechanisms underlying TOL and TRL deficits may serve to differentiate Alzheimer's from Parkinson's dementia, and may involve selective parietal system lesions.

Matching- and delayed matching-to-sample performance as measures of visual processing, selective attention, and memory in aging and alcoholic individuals.

Visual processing time, selective attention to visual cues, and memory for those cues were measured in groups of normal and alcoholic research participants within three different age ranges: young (35-45 yr), middle (46-59 yr) and older (60-70 yr). Performance across groups also was compared to that of alcoholic Korsakoff patients, known to have processing and attentional abnormalities. The matching-to-sample task was employed in which participants are required to match one of two laterally located response choices with a stimulus displayed in the center between them. Duration of the center sample stimulus varied between 20 and 500 msec, and delay between sample offset and response-choice (match) onset varied between 0 and 30 sec. Complexity of the sample stimulus also was varied, containing one or two dimensions (color and/or form). Levels of performance for all groups improved with increased sample stimulus durations, and were negatively related to a stimulus complexity and length of delay. Significant group differences in accuracy were evident with short stimulus exposures; the Korsakoff and older groups made more errors than the younger groups. Similarly, response times were influenced differentially by stimulus duration, stimulus complexity, and the delay between sample and matching stimuli, with young participants (alcoholics and controls) responding fastest. Results emphasize the contribution of processing deficits to other cognitive impairments in aging and alcoholic individuals, as well as the relative independence of aging and alcoholism.

Comparative neuropsychology and Korsakoff's syndrome. III--Delayed response, delayed alternation and DRL performance.

Performance of alcoholic Korsakoff patients was compared with that of patients with Huntington's disease. Broca's aphasia or alcoholism (without clinical signs of memory impairment) on delayed alternation (DA) and delayed response (DR) tests. Korsakoffs were impaired on both tasks, and Huntington patients were impaired on DA only. In a separate experiment, performance by Korsakoffs was compared to that of alcoholic and normal controls on four DRL schedules. Korsakoffs tended to be overresponsive, making errors of commission early within a schedule, and consequently, obtaining fewer reinforcements than the controls.

Cross-modal functions in alcoholism and aging.

Two experiments were performed to measure separate aspects of cross-modal functions in normal and alcoholic research participants: matching, and utilization of concepts. In Experiment 1, cross-modal equivalence-matching was measured, i.e. the ability to select in a second modality (e.g. vision), the same stimulus that was first presented in a different modality (e.g. touch). Experiment 2 measured cross-modal transfer of information about stimulus dimensions, i.e. the ability to recognize and use the concepts of texture and form, based upon prior experience solving tactual problems, to solve visual problems. Fifty-five normal and alcoholic research participants comprised the following five groups: 13 young normals (YN) and 10 young alcoholics (YA), 28-48 years of age; 13 older normals (ON) and 14 older alcoholics (OA), 50-71 years of age; and 5 alcoholic Korsakoff patients (K), 55-68 years of age. Separate subgroups of 9 age-matched ONs and 9 OAs were devised for purposes of statistical analyses of data involving the 5 Ks. Results of the experiments indicated that aging is associated with decline in tactual discrimination ability. Further, cross-modal functions appear to be compromised by alcoholic Korsakoff's disease, and--to a lesser extent--by the combined effects of alcoholism and normal chronological aging. Brain mechanisms important for normal cross-modal functions are discussed.

Alcoholism, aging, and functional cerebral asymmetries.

Reviews research concerning the possible relationship between cognitive decline and abnormal hemispheric asymmetries in alcoholic and aging individuals. Because the deteriorative effects of alcoholism on the central nervous system have suggested greater visuospatial than language-related functional impairments, numerous investigators had hypothesized that right-hemisphere integrity may be selectively disrupted (rather than the left hemisphere). Furthermore, performance on diverse perceptual and cognitive tests used to measure right-hemisphere functions in alcoholics had been observed to decline with normal chronological aging as well, thereby raising the possibility that certain neuropsychological deficits associated with alcoholism (presumably related to right-hemispheric decline) are identical to those associated with aging. However, an extensive review of empirical research findings on cerebral asymmetries both in alcoholics and in aging individuals suggested that their patterns of functional laterality are similar to those of normal controls.

Bilateral frontal lobe disease and selective delayed response deficits in humans.

The performance of patients with frontal lobe disease was compared with that of amnesic patients (with etiology of alcoholic Korsakoff's disease or surgically treated ruptured anterior communicating artery aneurysm) on tasks known to be sensitive to frontal lobe damage in nonhuman primates: delayed alternation (DA) and delayed response (DR). Alcoholic patients with no clinical memory impairment served as controls. Results showed that bilateral frontal lobe damage in humans is associated with impairment on both tasks. In addition, there was no relation between performances on DA and DR and performance on standardized tests of memory, a result strengthening the suggestion that the former tasks are not sensitive to anterograde amnesia in humans.

Visual and auditory spatial and nonspatial delayed-response performance by Korsakoff and non-Korsakoff alcoholic and aging individuals.

Thirty-six male alcoholics (13 with Korsakoff's syndrome) and 24 controls performed visual and auditory delayed-response tasks sensitive to prefrontal cortical damage in nonhuman primates. Korsakoff patients were consistently impaired compared with other subjects. Impairments by Korsakoff patients were evident when demands were placed on visual processing time (brief stimulus durations), and the deficits became exaggerated with increased demands on short-term memory. Under the most difficult experimental conditions, controls and non-Korsakoff alcoholics who were over 50 years old performed somewhat worse compared with younger groups 27-49 years old. Age-linked deficits were mild compared with Korsakoffs' deficits, and age-group differences disappeared with easier task demands. The results implicate cortical pathology in alcoholism and normal chronological aging and suggest that prefrontal damage accompanies alcoholic Korsakoff's syndrome.

Effects of dimepramine fumarate on physiological and cognitive behaviors of Parkinson patients.

Nine patients 55 to 74 years old with Parkinson's disease were tested before and after treatment with 50 to 225 mg dimepramine fumarate (CIBA G-31406) for about three weeks daily in order to determine the drug's effects on electrodermal responsiveness to a series of unpredictably occurring loud sounds. Twelve control subjects were tested and retested with the same procedure. In addition, the Parkinson patients received a number of cognitive tests before and after drug treatment. Results indicated that the drug tends to decrease autonomic arousal responses as measured by resting conductance levels, number of fluctuations in skin conduction per minute, orienting response, and habituation rate. These decreases in measures of arousal generally were accompanied by lowered performance scores on several tests of memory and temporal discrimination ability.

Association learning and recognition memory in alcoholic Korsakoff patients.

Association learning and recognition memory were examined in 8 male alcoholic Korsakoff patients (mean age 58), and in the following 4 groups of 10 men: non-Korsakoff alcoholics (mean age 59), nonalcoholic controls (mean age 64), younger alcoholics (mean age 36), and nonalcoholic controls (mean age 37). The tasks were modeled after those used for testing memory functioning in nonhuman primates. Association learning, defined as the ability to distinguish rewarded from equally familiar nonrewarded visual stimuli, was impaired in Korsakoff patients. Korsakoff patients also were impaired on recognition memory-the ability to discriminate familiar from novel items. Results support the view of loss of multiple memory functions in alcoholic amnesia. An effect of aging was indicated by differences in performance levels between younger and older groups of non-Korsakoff participants, although the latter were superior to the Korsakoff patients.

Selective attentional processing and the right hemisphere: effects of aging and alcoholism.

Thirty-seven nonalcoholic individuals (22 women, 15 men), ages 26-76, and 36 abstinent alcoholic individuals (11 women, 25 men), ages 31-74, participated in a cued-detection task that assessed right hemisphere (RH) functioning associated with aging and alcoholism. Young controls were less reliant on cues following RH activation, which is consistent with the view that the RH has an advantage because it has the ability to attend to a broader spatial array than does the left hemisphere (LH). This RH advantage was not obtained in older controls or alcoholic participants. The pattern of results for the older nonalcoholic participants indicated that they neither benefited from valid cues following LH activation nor exhibited enhanced processing on invalid cue trials following RH activation. The results for the alcoholic participants were consistent with RH functional decline, but did not support the view that alcoholism and aging have synergistic effects.

Iconic recognition of musical symbols in the lateral visual fields.

Subjects with formal musical training were tested tachistoscopically in order to obtain thresholds for recognizing single notes a staff, presented successively to the lateral visual fields. They were also tested on backward visual making of the same stimuli to determine the interstimllus interval needed to escape the masking effect (critical ISI). Response requirements in threshold and ISI conditions were nonverbal (depressing an organ key), or verbal (indicating the stimulus by name). Recognition threshold for notes were lower in the right visual field than in the left, and verbal responses were easier than manual responses in the threshold condition. However, critical ISIs were lower in the left field than in the right, and ISIs from the left visual field were lower with manual responses than with verbal responses. These findings support the idea that (a) threshold and ISI represent separate levels of perceptual processing, and (b) in trained subjects, the ability to recognize musical symbols may be governed by the left hemisphere, while the information-processing stage of iconic storage may occur in the right hemisphere.

Impairments of brain and behavior: the neurological effects of alcohol.

Chronic heavy drinking and alcoholism can have serious repercussions for the functioning of the entire nervous system, particularly the brain. These effects include changes in emotions and personality as well as impaired perception, learning, and memory. Neuropathological and imaging techniques have provided evidence of physical brain abnormalities in alcoholics, such as atrophy of nerve cells and brain shrinkage. At the cellular level, alcohol appears to directly affect brain function in a variety of ways, primarily by interfering with the action of glutamate, gamma-aminobutyric acid, and other neurotransmitters. Neurological disorders also can result from vitamin deficiency and liver disease, two health problems that commonly occur with alcoholism. Other hypotheses, based on factors such as aging, gender, and genetics, have been developed to explain various alcohol-related neurological consequences. Many pharmacological treatments to improve neuropsychological functioning in alcoholics have been tested, but none has proved entirely successful. With prolonged abstinence, however, slow recovery of cognitive functioning can occur in some cases.

Repetition priming of words and pseudowords in divided attention and in amnesia.

Repetition priming of novel stimuli (pseudowords) and stimuli with preexisting representations (words) was compared in two experiments. In one, 19 normal male subjects performed a lexical decision task with either focused or divided attention. In another, lexical decision performance was compared between 8 male Korsakoff patients and 8 alcoholic control subjects. In control conditions, repetition speeded responses to both stimulus types. Experimental conditions that minimized the contribution of episodic memory to task performance eliminated reaction time priming for pseudowords but not for words. However, in these same conditions, repetition increased the likelihood that pseudowords would be incorrectly classified. These results indicate that preserved repetition priming effects in amnesia do not solely reflect activation of representations in semantic memory.

Comparative neuropsychology of cortical and subcortical dementia.

The terms "cortical" and "subcortical" dementia are controversial; however, the clinical distinction between them is real. For example, although Alzheimer's and Parkinson's disease (prototypical of cortical and subcortical dementia, respectively) share clinical features, they differ in the presence of aphasia, apraxia, and agnosia in Alzheimer's disease but not in Parkinson's dementia. We review our studies aimed at clarifying the mechanisms underlying the differences between these neurological disorders. Experimental paradigms adopted from animal models were used to study the functional anatomy and neuropsychological characteristics of Alzheimer's and Parkinson's disease. The tasks administered include delayed alternation (DA) and delayed response (DR), which are sensitive to frontal system damage, and tactile discrimination learning (TOL) and reversal (TRL) paradigms sensitive to parietal system damage. Alzheimer's patients were significantly impaired on all tasks whereas Parkinsonians with dementia were impaired only on DR and TRL. Consideration of neuroanatomical and neuropsychological mechanisms involved in DA, DR, TOL, and TRL appears to have sharpened the distinction between Alzheimer's and Parkinson's dementia. Dementia in Alzheimer's disease may involve dorsolateral frontal, orbitofrontal and parietal systems. In contrast, dementia in Parkinson's disease may involve prominent dorsolateral frontal system damage.

Alcohol-related ERP changes in cognition.

This paper reviews five separate experimental studies concerning the acute or chronic effects of alcohol on late ERP components related to cognitive processes. The studies are evaluated for their adequacy in two arenas: (a) task relevance from a behavioral viewpoint, and (b) their ability to clarify the functional significance of alcohol-related ERP changes. Based upon the general trends of the results reported from the five individual laboratories conducting the investigations, it can be concluded that the P3 component is the most consistently altered of the four late ERP components considered (N1, N2, P2, P3). The finding of a reduced P3 amplitude was more reliable than the finding of increased P3 latency. Alterations in ERP components, when they did occur, occurred under the acute influence of ethanol, as well as in abstinent chronic alcoholics. All of the ERP findings reported were obtained using variations of signal detection procedures. Changes in ERP components did not always parallel performance changes, suggesting that aspects of psychological processes (e.g., attention and stimulus evaluation), presumed to underly ERPs' functional significance, did not directly reflect these processes.

Lack of laterality effect for monaural categorization of VOT and TOT stimuli.

Sixteen right-handed males were tested for lateral preference and consistency of identification of stimuli differing in voice-onset time (VOT) or tone-onset time (TOT). A continuum of 10 stimuli of each type was presented monaurally to the right and left ears, and reaction times (RTs) were recorded each time a participant indicated a choice between a voiced [da] and a voiceless [ta] alternative for VOT, or between the presence of one type of tone or another for TOT. Results indicated that both classes of stimuli were perceived as having unique boundaries, with the TOT boundary being lower than that of the VOT continuum. VOTs were identified more quickly than TOTs, and the two ears did not differ in consistency or speed of identification for either condition. Results cannot be used to support the idea that the two hemispheres process voice-onset time differently than tone-onset asynchronies. In view of the absence of a right ear advantage for VOT, however, the use of a monaural task for eliciting hemispheric asymmetries is not recommended.

Visual laterality patterns for the perception of emotional words in alcoholic and aging individuals.

OBJECTIVE: This study evaluated hypotheses concerning alcohol-related cerebral dysfunction: (1) alcoholism, like normal chronological aging, has a more detrimental effect upon functions controlled by the right hemisphere of the brain than functions controlled by the left hemisphere; (2) interhemispheric transfer dysfunction is associated with alcoholism and aging; and (3) alcoholism and aging act synergistically. METHOD: The participants were 61 right-handed men: 18 young (ages 30 to 49 years) and 14 older (50 to 69 years) detoxified abstinent alcoholics and 14 young and 15 older healthy nonalcoholic controls. In a perceptual laterality paradigm, emotional and nonemotional words were presented to the left or right visual fields, followed by a visual masking stimulus. The participants were asked to judge the emotional valence of each word (positive, negative or neutral) and to respond verbally or manually (button presses). The dependent variable was the Critical Interstimulus Interval needed to escape the backward-masking effect. RESULTS: The alcoholics showed a significant right visual field advantage in both response mode conditions, whereas the controls did not. In addition, older alcoholics showed a selective impairment in processing negative words. CONCLUSIONS: The findings support the suggestion that alcoholics may have deficient right-hemisphere functioning. Since both the young and older alcoholic groups showed similar right visual field advantages, the idea of synergism between alcoholism and aging with respect to perceptual asymmetries was not supported.