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PubMed1991

(+-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine, an M1 selective cholinergic agonist, attenuates cognitive dysfunctions in an animal model of Alzheimer's disease.

AF102B [(+-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine], a structurally rigid analog of acetylcholine, was investigated in a number of neurochemical, pharmacological and behavioral tests related to cholinergic functions. AF102B induced atropine-sensitive contractions of isolated guinea pig ilea and trachea preparations with EC50 values of 3.5 and 3 microM being 87- and 1.3-fold less potent than acetylcholine, respectively. Binding studies using the radioligands pirenzepine, cis-dioxolane and quinuclidinyl benzilate in rat cerebral cortex and quinuclidinyl benzilate in cerebellar homogenates indicated that AF102B was a potent and highly selective M1-type muscarinic probe, being more selective for M1 receptors than oxotremorine, carbachol and AF102A (the trans-isomer of AF102B). AF102B had a 3-fold higher apparent affinity for M1 receptors than the prototype M1 agonist, McN-A-343, cis- and trans-AF30 (other rigid analogs of acetylcholine). Treatment of rat cortical homogenates with Cu++ ions did not modify the affinity observed for the muscarinic antagonists atropine, scopolamine and pirenzepine, whereas increasing the proportion of high affinity sites for the agonists oxotremorine-M, carbachol and McN-A-343. The apparent affinity of AF102B also increased by Cu++ treatment suggesting that this compound interacts with rat cerebral cortex muscarinic receptors as an agonist. AF102B did not affect high affinity choline transport, choline acetyltransferase and acetylcholinesterase activities in rat brain preparations. In rats treated with AF64A (the cholinotoxin ethylcholine aziridinium ion; 3 nmol/2 microliters/side i.c.v.), AF102B (1 mg/kg p.o. or i.p.), AF102A (1 mg/kg i.p.), cis-AF30 (1 mg/kg, i.p.) and physostigmine (0.06 mg/kg i.p.), each reversed cognitive impairments in a step-through passive avoidance task. Both AF102B and AF102A (1 mg/kg i.p.), but not physostigmine (0.1 mg/kg i.p.), were effective also in reversing reference memory impairments in a Morris water maze test. Repetitive administrations of AF102B (0.2 mg/kg/day i.p.) improved AF64A-induced working memory deficits in the Morris water maze test, but did not affect open field behavior. The data show that the selective M1 agonist AF102B can restore AF64A-induced cognitive impairments, without producing adverse central and peripheral side effects at the effective doses and this can indicate its potential use for the treatment of Alzheimer's disease.

Alzheimer Disease↗
PubMed1998

Visual cognitive dysfunction in depression: an event-related potential study.

The P3(00) event-related potentials (ERPs) elicited by visual stimuli in two visual tasks were assessed in depressed patients (12 patients with major depression and 11 patients with bipolar disorder) and compared with those of 20 age-matched normal controls. At remission, the ERPs from 18 of the depressed patients were again recorded. The visual oddball (VO) paradigm presented both target and standard visual stimuli and the simple visual (SV) paradigm presented a target but no standard visual stimulus. Subjects performed the VO task significantly less accurately than the SV task, as reflected by the behavioral measures (reaction-time and task accuracy). Depressed patients of the bipolar group showed longer P3 peak latency for the VO task and no change in P3 amplitude. No significant differences were found in any other ERP component between the groups. During remission, slowing RTs and reduced P3 peak latencies were observed for both major depression and bipolar disorder groups. Thus, the P3 ERP may be an index of the contribution of the slowed central processing to psychomotor retardation in clinically homogenous samples of depressive patients performing an appropriately demanding task.

Adult↗
PubMed2000

Intrauterine methylmercury intoxication. Consequence of the inherent brain lesions and cognitive dysfunction in maturity.

We studied the effects of intrauterine neurotoxicity by methylmercury (MeHg) on the postnatal developing and adult stages of rats. We used offspring delivered from dams that had been given 1 mg/kg/day methylmercury chloride for 5 pregestational days and throughout pregnancy. Histopathological examination of the brains of a proportion of the offspring on postnatal days 1 (P1) and P3 revealed degenerative neurons in the brain stem and the limbic system, including the hippocampus and the amygdala. At P7 and P14, degenerative neurons were indiscernible, but reactive astrocytosis remained in the brain stem. At P70 and P180, the brains seemed to have developed well. However, in behavioral analyses performed at 6 months of age, MeHg-exposed rats showed a significant learning disability in the passive avoidance response compared with controls, but no differences in water maze performance. Furthermore, morphometric analysis of the amygdala and hippocampus revealed significantly fewer neurons in both areas in the MeHg-exposed rats. Thus, chronic intrauterine exposure to low-dose MeHg induces a decrease in neuron population in the limbic system, and the offspring have impaired higher brain function.

Age Factors↗
PubMed1996

Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy.

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment. Intraventricular administration of NGF is necessary because NGF will not cross the blood-brain barrier (BBB). Here we have used a novel carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. In our experiment, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate or a control solution (a mixture of unconjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF injections resulted in a significant improvement in spatial learning in previously impaired rats but disrupted the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatial learning. These results indicate the potential use of the transferrin receptor antibody delivery system for treatment of CNS disorders with neurotrophic proteins.

Aging↗
PubMed1981

Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation.

Intellectual and other neuropsychological dysfunctions have been observed in survivors of childhood acute lymphocytic leukaemia (ALL). The possible relationship of therapy to these dysfunctions was investigated in a prospective study of children with newly diagnosed ALL seen at the Children's Hospital of Philadelphia. They were evaluated with standardised intelligence tests during the first month of treatment and periodically thereafter. There were two therapy schedules--one using standard drugs for induction and maintenance, the other a more intensive schedule. Central-nervous-system prophylaxis (2400 rad cranial radiation and six doses of intrathecal methotrexate) was given to all. Significant reductions were found in overall IQ score for the majority of children, younger patients being most affected. More extensive testing of surviving children, with and without decline in IQ, all of whom were normal on the first test, revealed patterns of functional deficits and residual strengths that could not be characterised with IQ testing alone. These deficits, which could affect learning and academic performance, were not seen in six children studied years after receiving similar chemotherapy that included intrathecal and oral methotrexate but not cranial irradiation.

Adolescent↗
PubMed1998

Cognitive dysfunction and histological findings in rats with chronic-stage contusion and diffuse axonal injury.

The Morris water maze (MWM) technique is well known as a prominent method of evaluating learning acquisition and memory retention impairments in rats. We previously reported on a modified fluid percussion device that is able to consistently produce experimental cortical contusion (CC) and diffuse axonal injury (DAI) in separate groups of rats. The purpose of the present protocol is to evaluate the differences in learning acquisition and memory retention impairments between these two types of injured rats in the chronic stage using the MWM technique. CC and DAI rats are respectively induced by lateral and midline fluid percussion. We also compare the histological differences between these two different types of traumatic brain injury. The results show statistically significant differences in learning acquisition impairment between the sham and CC rats and between the sham and DAI rats. However, a difference in memory retention impairment was expected to be seen only between the sham and DAI rats. Histologically, the loss of CA3 pyramidal cells in the hippocampus was observed ipsilaterally in the CC and bilaterally in DAI. Neuronal cell loss was observed in bilaterally in layer II of the entorhinal cortex in DAI, but not in CC.

Animals↗
PubMed1997

Estrogen alleviates cognitive dysfunction following transient brain ischemia in ovariectomized gerbils.

Capability of estrogen to alleviate spatial-learning deficits due to brain ischemia was evaluated in ovariectomized gerbils. Thirty-nine ovariectomized gerbils were physically trained to swim in a 90 cm-diameter round pool. The half of the ovariectomized animals received subcutaneous implantation of a Silastic capsule of estrogen, 1 week before ischemic assault. Transient brain ischemia was accomplished on experimental day 1 by bilateral clipping of the common carotid artery for 15 min under pentobarbital and ketamine anesthesia. On day 3 and onwards, daily Morris water-maze task was imposed. Although estrogen-treated non-ischemic animals spent longer time in the water, their distances swam were not different from non-treated animals: estrogen had no effect on the spatial learning to take the shortest distance to get to the submerged table. In the ovariectomized non-treated gerbils, ischemia prolonged the time in the water and lengthened the distance swam. Among the ischemic gerbils, those given estrogen swam a significantly shorter distance than the non-treated animals. The results indicate that estrogen alleviates the ischemia-induced deficits in the acquisition of the water-maze task. The results also defy previous association of estrogen with decreased acquisition of the water-maze task, which was based principally on the prolonged time in the water.

Animals↗
PubMed2005

Delirium: acute cognitive dysfunction in the critically ill.

PURPOSE OF REVIEW: The management of sepsis and the multiple organ dysfunction syndrome has traditionally been centered on dysfunction of organs other than the brain (e.g., heart, lungs, or kidneys), although the brain is one of the most prevalent organs involved. Recent studies indicate that nonpulmonary acute organ dysfunction may contribute significantly to mortality and other important clinical outcomes. Acute confusional states (delirium) occur in 10 to 60% of the older hospitalized population and in 60 to 80% of patients in the intensive care unit, yet go unrecognized by the managing physicians and nurses in 32 to 66% of cases. Delirium is an important independent prognostic determinant of hospital outcomes, including duration of mechanical ventilation, nursing home placement, functional decline, and death. Recently, new monitoring instruments have been validated for monitoring of delirium in noncommunicative patients receiving mechanical ventilation. Hence, critical care physicians and nurses should routinely assess their patients for delirium and develop strategies for its prevention and treatment. RECENT FINDINGS: This state-of-the-art review discusses in depth the delirium monitoring instruments, the pathophysiology and risk factors of delirium, its prognostic implications, and strategies (including ongoing clinical trials) to prevent and treat delirium. SUMMARY: Delirium is extremely common and has significant prognostic implications in critically ill patients. Routine monitoring and a multimodal approach to prevent or reduce the prevalence of delirium are of paramount importance.

Aged↗
PubMed2006

Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors.

Previous pharmacological experiments provide conflicting findings that describe both facilitatory and inhibitory effects of neuronal histamine on learning and memory. Here, we examined learning and memory and synaptic plasticity in mice with a null mutation of gene coding histamine H1 or H2 receptor in order to clarify the role of these receptors in learning and memory processes. Learning and memory were evaluated by several behavioral tasks including object recognition, Barnes maze and fear conditioning. These behavioral tasks are highly dependent on the function of prefrontal cortex, hippocampus or amygdala. Object recognition and Barnes maze performance were significantly impaired in both H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice when compared to the respective wild-type (WT) mice. Conversely, both H1KO and H2KO mice showed better auditory and contextual freezing acquisition than their respective WT mice. Furthermore, we also examined long-term potentiation (LTP) in the CA1 area of hippocampus in H1KO and H2KO mice and their respective WT mice. LTP in the CA1 area of hippocampus was significantly reduced in both H1KO and H2KO mice when compared with their respective WT mice. In conclusion, our results demonstrate that both H1 and H2 receptors are involved in learning and memory processes for which the frontal cortex, amygdala and hippocampus interact.

Analysis of Variance↗
PubMed1997

[Radiotherapy-induced cognitive dysfunction in 4-months-old male Wistar rats]].

PURPOSE: Behavioral dysfunction of memory process arising 4 months after whole brain irradiation (30 Gy/10 fractions/12 days) has been demonstrated in 16-27 month old rats, as compared with non irradiated rats. This study was therefore aimed at delivering the same irradiation in young rats and comparing results with those previously obtained in old rats. MATERIAL AND METHODS: Thirty-three 4-month old rats were included into the study. Eighteen received whole brain irradiation (30 Gy/10 fractions/12 days), and 18 were given sham irradiation. Sequential behavior studies were done before irradiation and during the 7 months following irradiation. RESULTS: Significant decrease in memory function was observed in irradiated rats 1 month (p < 0.001), 3 months (p < 0.013), and 6 months (p = 0.007) post-irradiation. This was accompanied by learning deficit 1 month (p = 0.01), 4.5 months (p = 0.03), and 7 months (p = 0.009) post-irradiation. CONCLUSION: Response to radiation therapy observed in young rats differed from that observed in old rats. Young rats showed earlier decrease in memory function than old rats, but this deficit was followed by partial recovery. Learning deficits also arised earlier in young rats than in old rats. In two cases this deficit was permanent.

Age Factors↗
PubMed2006

Effect of Withania somnifera root extract on reserpine-induced orofacial dyskinesia and cognitive dysfunction.

Tardive dyskinesia is one of the major side effects of long-term neuroleptic treatment. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of tardive dyskinesia. Repeated treatment with reserpine (1.0 mg/kg) on alternate days for a period of 5 days (days 1, 3 and 5) significantly induced vacuous chewing movements and tongue protrusions in rats. Chronic treatment with Withania somnifera root extract (Ws) for a period of 4 weeks to reserpine treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced vacuous chewing movements and tongue protrusions. Reserpine treated animals also showed poor retention of memory in the elevated plus maze task paradigm. Chronic Ws administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that chronic reserpine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the brains of rats. Chronic reserpine treated rats showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Chronic administration of Ws root extract dose dependently (50 and 100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The major findings of the present study indicate that oxidative stress might play an important role in the pathophysiology of reserpine-induced abnormal oral movements. In conclusion, Withania somnifera root extract could be a useful drug for the treatment of drug-induced dyskinesia.

Animals↗
PubMed2004

Reversal of reserpine-induced orofacial dyskinesia and cognitive dysfunction by quercetin.

Tardive dyskinesia (TD) is a serious neurological syndrome associated with long-term administration of neuroleptics to humans and experimental animals. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells or may be due to free radicals as a product of high synaptic dopamine levels. Quercetin is a bioflavonoid with strong antioxidant properties. Repeated treatment with reserpine (1.0 mg/kg) on each other day for a period of 5 days (days 1, 3 and 5) significantly induced vacuous chewing movements (VCMs) and tongue protrusions (TPs) in rats. Chronic treatment with quercetin for a period of 4 weeks to reserpine-treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced VCMs and TPs. Reserpine-treated animals also showed poor retention of memory in elevated plus-maze task paradigm. Chronic quercetin administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that chronic reserpine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the brains of rats. Chronic reserpine-treated rats showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Chronic administration of quercetin dose dependently (50-100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The results of the present study clearly indicated that quercetin has a protective role against reserpine-induced orofacial dyskinesia and memory impairment. Consequently, the use of quercetin as a therapeutic agent for the treatment of TD should be considered.

Animals↗
PubMed2000

Effect of Indian Hypericum perforatum Linn on animal models of cognitive dysfunction.

The effect of a standardised 50% ethanolic extract of Indian Hypericum perforatum (IHp) was investigated for its putative nootropic activity on various experimental paradigms of learning and memory, viz. transfer latency (TL) on elevated plus-maze, passive avoidance (PA), active avoidance (AA), scopolamine and sodium nitrite induced amnesia (SIA & NIA) in albino rats. Pilot studies indicated that single dose administration of IHp had little or no acute behavioural effects, hence the extract of IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.), once in daily for three consecutive days, while piracetam (500/kg, i.p.), a clinically used nootropic agent, was administered acutely to rats as the standard drug. Control rats were treated with equal volume of vehicle (0.3% carboxymethyl cellulose (CMC)). IHp and piracetam when given alone shortened the TL on day 1, 2, 9 and also antagonised the amnesic effects of scopolamine and sodium nitrite on the TL significantly. IHp had no significant per se effect on the retention of the PA in rats. Only the higher dose (200 mg/kg, p.o.) produced a significant reversal of scopolamine induced PA retention deficit but no significant reversal was observed with sodium nitrite. Piracetam showed significant per se facilitatory effect on PA retention and also reversed the scopolamine and sodium nitrite induced impaired PA retention. In the AA test, IHp in both the doses, and piracetam, facilitated the acquisition and retention of AA in rats and the IHp effects were found to be dose dependent. Both the doses of IHp and piracetam significantly attenuated the scopolamine and sodium nitrite induced impaired retention of AA. These results indicate a possible nootropic action of IHp, which was qualitatively comparable with that induced by piracetam.

Amnesia↗
PubMed1996

Reversible modification of GABAA receptor subunit mRNA expression during tolerance to diazepam-induced cognition dysfunction.

Benzodiazepines (BZs) that are endowed with full positive allosteric modulatory (FAM) activity on GABAA receptors cause anterograde amnesia in both animals and humans. In rats subjected to a delayed object recognition test, diazepam, endowed with FAM activity, exerted an amnesic action, whereas BZs endowed with partial allosteric modulatory (PAM) activity on GABAA receptors, such as imidazenil, failed to induce amnesia, even if administered at doses five times higher than those equipotent to a standard anticonvulsant dose of diazepam (17.6 mumol/kg/os). After discontinuation of 14 days' treatment with vehicle, diazepam, or imidazenil (three times daily with increasing doses starting from 17.6 mumol/kg/os for diazepam and 2.5 mumol/kg/os for imidazenil), we compared the persistence of tolerance to the amnesic effect of diazepam with the persistence of the changes in the context of four (alpha 1, alpha 5, gamma 2L, gamma 2S) GABAA receptor subunit mRNAs in the fronto-parietal motor (FrPaM) cortex and the hippocampus. Rats receiving the long-term treatment with diazepam developed a tolerance to the amnesic effect of this drug and showed a decrease (30-50%) in the expression of mRNAs encoding for alpha 1 gamma 2L, gamma 2S GABAA receptor subunits, an increase, by approximately 30%, of the expression of mRNA of the alpha 5 subunit in the FrPaM cortex and a decrease, by approximately 25%, in the expression of mRNA, of the alpha 1 subunit in the hippocampus. These changes of subunit mRNA expression and the tolerance to the amnesic effect of diazepam returned to control values 72 hr after termination of the long-term treatment with diazepam. No tolerance to the amnesic effect of diazepam and no changes in GABAA receptor subunit mRNA expression were found in rats undergoing long-term treatment with imidazenil.

Animals↗
PubMedDate not supplied

Postnatal handling attenuates certain neuroendocrine, anatomical, and cognitive dysfunctions associated with aging in female rats.

Hippocampal degeneration with aging is associated with increased hypothalamic-pituitary-adrenal (HPA) activity and, in male rats, both are attenuated by postnatal handling. Considering the important sex differences in the effects of handling and in HPA responses to stress in older rats, we have examined the effects of postnatal handling on aging in females. Female, Long-Evans rats were handled (H) during the first 3 weeks of life and later compared with nonhandled (NH) controls at various ages. Handling resulted in permanently increased hippocampal type II, glucocorticoid receptor binding. Relative to H females, NH females showed increased basal corticosterone levels in later life and hypersecreted corticosterone following stress at all ages examined. Both effects are similar to those reported in males. However, unlike males, H and NH females did not differ in corticosterone levels achieved during stress, a finding that may be related to sex-dependent effects of handling on pituitary transcortin receptors. There were no differences in hippocampal neuron density in 6-month-old animals. However, the older NH animals showed considerable neuron loss in the CA1 and CA3 hippocampal cellfields. There was little or no neuron loss in the H animals. Finally, the NH animals exhibited age-related spatial memory impairments, such that by 24 months of age the performance of the NH females was profoundly worse than that of the younger NHs and same-aged H animals. These data suggest that early handling permanently alters CNS systems that regulate hypothalamic-pituitary-adrenal (HPA) function, although the effect may depend on the gender of the animal. In both males and females, however, handling appears to prevent (or minimize) increased adrenal secretion in later life and to attenuate hippocampal cell loss and spatial memory impairments.

Aging↗
PubMed1995

[Cognitive dysfunction following anterior communicating artery aneurysm rupture. Comparison with alcoholic Korsakoff syndrome on neuropsychological performance].

The present study aims to compare neuropsychological performance of patients following anterior communicating artery aneurysm rupture (ACoA) with that of patients with alcoholic Korsakoff syndrome (AKS). Fifteen ACoA patients and ten age-and education-matched AKS patients were included in the study. All the patients were tested at least one year post onset of their illness at a stable condition. The WAIS and forward digit span scores of AKS were also matched to ACoA, and simple attention and general intelligence were well preserved both in ACoA and AKS. Frontal function as measured by the Wisconsin card sorting test (Keio version) (KWCST) was equivalently impaired in the two groups. Anterograde memory as measured by Wechsler memory scale subtests, serial seven word learning test, Rey auditory verbal learning test, and logical memorizing test (Luria's paired word-picture association), was more severely impaired in AKS than ACoA in contrast to the comparable attention, intelligence, and frontal function: (1) memory tasks with low correlations to KWCST (serial word learning tasks and paired verbal associates), reflecting primary simple serial memorizing, and (2) memory tasks with high correlations to KWCST (logical memory and logical memorizing), reflecting higher and complicated strategic mnemonic activities. However, the correlations between these anterograde memory subtests and KWCST were substantially equivalent in ACoA and AKS. This suggests that the differences in anterograde amnesia demonstrated in ACoA and AKS may be of quantitative, not of qualitative property. The extent of deficits in semantic encoding as measured by Wickens' release from proactive interference paradigm (PI release) was also milder in ACoA than AKS. Both AKS and ACoA failed to show PI release in contrast to normal PI release demonstrated in age-matched ten healthy subjects. PI release in ACoA, however, was in between AKS and healthy subjects. The results were interpreted in the light of a recently postulated hypothesis that a combination of frontal lobe damage and memory impairment is crucial for causing a deficit in semantic encoding. The extent of damage in the memory circuit in ACoA may be variable, which may result in milder degree of anterograde amnesia and semantic encoding than AKS in the present study.

Alcohol Amnestic Disorder↗
PubMed2000

Validity of questionnaires for assessing dysfunctional cognitions in bulimia nervosa.

OBJECTIVE: This research investigated the validity of the Bulimic Cognitive Distortions Scale and the Mizes Anorectic Cognitions Questionnaire. The ability of these questionnaires to discriminate among individuals with bulimia, restrained eaters, and normals was also investigated. METHOD: Scores on these retrospective self-report questionnaires were compared to cognitions assessed via in vivo thought-sampling. Cognitions of 15 women with bulimia nervosa, 15 restrained eaters, and 15 non-eating disordered women were assessed. RESULTS: Results indicated that both the BCDS and the MAC successfully discriminated among individuals with bulimia, restrained eaters, and normals, and adequately measured in vivo attitudes and beliefs associated with food and eating, weight and body-image, and low self-efficacy. DISCUSSION: These findings support the continued use of both the BCDS and the MAC.

Adolescent↗