MRI correlates of executive dysfunction in patients with ischaemic stroke

Executive dysfunction (ED) may lead to problem behaviour and impaired activities of daily living in many neuropsychiatric disorders, but the neuroanatomical correlates of ED are still not well known. Different aspects of executive functions were studied by widely used neuropsychological tests in 214 elderly patients 3 months after ischaemic stroke, and a sum score of eight different measures was counted in each patient. The number and site of brain infarcts as well as severity and location of white matter lesions (WMLs) and brain atrophy on magnetic resonance imaging were recorded and compared between patients with and without ED. ED was present in 73 (34.1%) of the 214 patients. The mean frequency of brain infarcts in the brain and in the left hemisphere was higher in the patients with ED. Lesions affecting the frontal-subcortical circuits (e.g. pallidum, corona radiata or centrum semiovale) were more frequent in patients with ED than in those without. Also, patients with pontine brain infarcts frequently had ED, but this may have been due to more extensive ischaemic changes in these patients in general. Mean number of brain infarcts affecting the pons and posterior centrum semiovale on the left side, moderate to severe medial temporal atrophy, the Fazekas white matter score, the Mini-Mental State Examination score and low education were independent correlates of ED. Brain infarcts and WML affecting the frontal-subcortical circuits or the pons may increase risk for ED in stroke patients.     

Poststroke depression and lesion location revisited

Seventy patients with one brain infarct on magnetic resonance imaging (MRI) were studied 3 months after ischemic stroke by a standardized protocol to detail side, site, type, and extent of the brain infarct, as well as severity of white matter lesions and brain atrophy. Depression was diagnosed by DSM-III-R and DSM-IV criteria. The brain infarcts that affected structures of the frontal-subcortical circuits, (i.e., the pallidum and caudate, especially on the left side) predisposed stroke patients to depression. The size of the infarcts at these sites in the depressed patients was larger. Using a logistic regression analysis, the authors found that a brain infarct that affected pallidum was a strong independent MRI correlate for poststroke depression (odds ratio = 7.2).     

Magnetic resonance imaging correlates of depression after ischemic stroke

BACKGROUND: Depression affects up to 40% of patients with ischemic stroke. The relationship between site and size of brain infarcts and poststroke depression is still not well characterized. Further possible contribution and interaction of white matter lesions and brain atrophy has not been studied previously. We conducted a magnetic resonance image-based study of the radiologic correlates of depression in a large, well-defined series of patients with ischemic stroke. METHODS: Modified DSM-III-R and DSM-IV criteria were used to diagnose depressive disorders during a comprehensive psychiatric evaluation in 275 of 486 consecutive patients aged 55 to 85 years 3 to 4 months after ischemic stroke. A standardized magnetic resonance imaging protocol detailed side, site, type, and extent of brain infarcts and extent of white matter lesions and brain atrophy. RESULTS: Depressive disorders were diagnosed in 109 patients (40%). Patients with depression had a higher number and larger volume of infarcts affecting the prefrontosubcortical circuits, especially the caudate, pallidum, and genu of internal capsule, with left-sided predominance. Extent of white matter lesions and atrophy did not differ in patients with and without depression. Independent correlates of poststroke depression in a logistic regression model were mean frequency of infarcts in the genu of internal capsule on the left side (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.0-10.1), mean frequency of infarcts in the pallidum of any side (OR, 1.6; 95% CI, 1.1-2.3), and mean volume of infarcts in the right occipital lobe (OR, 0.98; 95% CI, 0.96-0.99). CONCLUSION: Lesions affecting the prefrontosubcortical circuits, especially on the left side, are correlates of depression after ischemic stroke.     

A two-year longitudinal study of poststroke mood disorders. In-hospital prognostic factors associated with six-month outcome

In a prospective study of mood disorders in stroke patients, variables obtained during the acute hospitalization were examined for their relationship to outcome at either 3- or 6-month follow-up. Distance of the lesion on computerized axial tomography scan from the frontal pole in patients with left anterior infarcts was significantly associated with severity of depression at 3 and 6 months poststroke. In addition, intellectual and functional physical impairment in-hospital were significantly correlated with severity of depression and social functioning scores at 3 and 6 months poststroke. Thus, patients who develop depression during the first 6 months poststroke may be responding to the severity of their impairment whereas the patients who develop depressions during the acute poststroke period may have a neuroanatomical and neurophysiological basis for their depression. Although other explanations might be proposed, the dynamic nature of the relationship between depression and associated variables during the first 6 months poststroke indicates that etiology of poststroke depression may be different depending upon the time of onset of the depression after brain injury.     

Pathological correlates of poststroke depression in elderly patients.

OBJECTIVE: The authors examined the relationship between poststroke depression and location of stroke. METHODS: They performed a clinicopathological analysis of 95 consecutively autopsied elderly initial-stroke survivors. RESULTS: The severity of brain vessel arteriosclerosis and frequency of brain vascular lesions were not significantly different between 21 cases with poststroke depression and 74 cases without. Earlier death was the only variable significantly associated with poststroke depression. No lesion pattern characterized the depression group. CONCLUSIONS: Neuropathological data confirm that depression is associated with worse prognosis in elderly stroke patients and lend support to the hypothesis that psychological rather than neurological factors are the main determinants of poststroke depression.     

Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update

Frontal-subcortical circuits form the principal network, which mediate motor activity and behavior in humans. Five parallel frontal-subcortical circuits link the specific areas of the frontal cortex to the striatum, basal ganglia and thalamus. These frontal-subcortical circuits originate from the supplementary motor area, frontal eye field, dorsolateral prefrontal region, lateral orbitofrontal region and anterior cingulate portion of the frontal cortex. The open afferent and efferent connections to the frontal-subcortical circuits mediate coordination between functionally similar areas of the brain. Specific chemoarchitecture and multiple neurotransmitter interactions modulate the functional activity of each circuit. Dorsolateral prefrontal circuit lesions cause executive dysfunction, orbitofrontal circuit lesions lead to personality changes characterized by disinhibition and anterior cingulate circuit lesions present with apathy. The neurobiological correlates of neuropsychiatric disorders including depression, obsessive-compulsive disorder, schizophrenia and substance abuse, imply involvement of frontal-subcortical circuits.     

Frontal-subcortical circuitry and behavior

The neuropsychiatric manifestations of neurodegenerative diseases are closely linked to neurocircuitry defects. Frontal-subcortical circuits, in particular, are effector mechanisms that allow the organism to act on its environment. In this paper, we present the three main frontal-subcortical circuits: the dorsolateral prefrontal circuit allows the organization of information to facilitate a response; the anterior cingulate circuit is required for motivated behavior; and the orbitofrontal circuit allows the integration of limbic and emotional information into behavioral responses. Impaired executive functions, apathy, and impulsivity are hallmarks of frontal-subcortical circuit dysfunction. A variety of other neuropsychiatric disorders, such as Tourette's syndrome, Huntington's disease, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, schizophrenia, and mood disorders may result from disturbances that have a direct or indirect impact on the integrity or functioning of these loops.     

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1beta, TNF-alpha or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1beta, TNF-alpha or even IL-18, in patients with poststroke depression.     

Relationship between event-related potentials and frontal-subcortical dysfunction in Parkinson's disease

Cognitive impairment in Parkinson's disease (PD) has been determined to be due to the interruption of frontal-subcortical neural circuits. To evaluate which kind of frontal-subcortical dysfunction may be present and the relationship of this dysfunction with P300 in PD patients, non-demented PD patients and controls were rendered for comprehensive Frontal Test Battery and P300 assessments. PD patients manifested significantly with frontal dysfunction and revealed a good correlation between P300 and executive dysfunction. We conclude that PD patients may manifest with cognitive impairment related to frontal dysfunction, and P300 may be an indicator reflecting the evolution of dysexecutive syndrome.     

Relationship Between Mood,Thinking, and Walking: A Systematic Review Examining Depressive Symptoms,Executive Function,and Gait

Prior literature has proposed that the coexistence of late-life depression, executive dysfunction and impaired gait speed may constitute a specific phenotype in older adults with a possible shared brain mechanism. All three conditions are independently associated with negative health outcomes including impaired function, risk of falling, and reduced quality of life. However, the existence, etiology, and implications of having all three conditions as a unitary triad remain unclear. This systematic review examined the literature to assess the consistency of this triad and to explore the possible role of frontal-subcortical circuitry in its etiology. English language literature that assessed mood, executive function, and gait speed using a validated tool in human participants over age 65 were included for this review. Following the PRISMA guidelines, 15 studies including 11,213 participants met criteria for inclusion in this study. The triad's existence was supported by 12 of the 15 studies (80%), including 4 longitudinal studies involving 368 participants. A prevalence of 17% was reported in one population study. The three included intervention studies provided mixed results regarding the benefit of pharmacologic and exercise interventions. Two studies assessed the association between presence of white matter hyperintensities and the triad, with one study finding a significant longitudinal relationship with periventricular white matter hyperintensities. Vascular risk factors were also commonly associated with this triad. Taken together, the relationship between this triad, the vascular depression hypothesis, and frontal-subcortical pathology is suggested. Further longitudinal research is needed to further clarify the etiology and clinical relevance of this concomitant prescence oflate-life depression, executive dysfunction and impaired gait speed.     

Neuroanatomical correlates of executive functioning in depressed adults with type 2 diabetes

Depression is often comorbid with type 2 diabetes. Depression may increase vulnerability to and/or exacerbate existing cognitive deficits. Little is known about the brain pathophysiology underlying depression and cognitive abnormalities in diabetes. The aim of this study was to examine the relationship of orbitofrontal and anterior cingulate volumes with executive functioning and attention/processing speed in type 2 diabetic participants with and without major depression. A total of 21 diabetic participants with major depression, 23 diabetic participants with no depression, and 22 healthy controls were compared. Using brain magnetic resonance imaging, volumetric measures of the prefrontal cortex were examined in relation to executive functioning and attention/processing speed. Partial correlations suggested a significant positive relationship between right orbitofrontal regions and executive functioning in the group with diabetes and depression only, indicating that neurobiological changes in the orbitofrontal region may contribute to observed cognitive dysfunction.     

The clock drawing test as a measure of executive dysfunction in elderly depressed patients

The aims of this research were to determine whether performance on the Clock Drawing Test (CDT) could accurately distinguish between older patients with depression and older patients with depression and previously undocumented executive dysfunction and to determine if there was a correlation between CDT and depression severity. The authors studied 52 patients consecutively admitted to a geriatric psychiatry inpatient unit of a university hospital who met DSM-IV criteria for major depression or depression not otherwise specified but had no concurrent diagnosis of dementia. All the subjects completed the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (DRS), and the CDT, as well as the Geriatric Depression Scale (GDS). The patients were divided into 2 subgroups based on the DRS score: <129 (cognitive impairment) versus = 129. Results indicated that the depressed patients with a score of DRS <129 had significantly lower CDT scores than did patients with DRS = 129 and normal comparison subjects (P< .01). The results support the hypothesis that CDT score is lower in elderly depressed patients with executive dysfunction versus nondepressed seniors as well as depressed patients without executive dysfunction.     

MRI pontine hyperintensity after supratentorial ischemic stroke relates to poor clinical outcome

BACKGROUND AND PURPOSE: MRI studies in patients with atherosclerosis often reveal ill-defined hyperintensity in the pons on T2-weighted images. This pontine hyperintensity (PHI) does not fulfill the criteria of a brain infarct, and its clinical relevance is not established. We examined the frequency, as well as the radiological and clinical correlates, of PHI in poststroke patients. METHODS: Three hundred nineteen patients were studied 3 months after supratentorial ischemic stroke with the use of 1.0-T MRI. Brain infarcts, atrophy, white matter hyperintensities, and PHI were registered. The clinical outcome was assessed 3 and 15 months after the stroke. RESULTS: Of the patients, 152 (47.6%) had PHI. The risk factors for stroke did not differ in patients without or with PHI. PHI was related to a higher frequency (P=0.002) and larger volume (P<0.001) of supratentorial brain infarcts, to parietal (P=0.020) and temporal (P=0.002) atrophy, to central atrophy (P< or =0.040), and to white matter hyperintensity grade (P<0.001). Brain infarcts that affected the corpus striatum (putamen, caudate, and pallidum) (P< or =0. 011) or pyramidal tract (P<0.001) were more frequent in patients with PHI. The 3- and 15-month outcomes were worse in patients with PHI (P< or =0.004). The total volume of brain infarcts (OR 1.22), mean atrophy (OR 3.59), and PHI (OR 3.76) were independent correlates of a poor 15-month outcome. CONCLUSIONS: PHI after supratentorial ischemic stroke deserves attention because it relates to poor clinical outcome.     

Group and case study of the dysexecutive syndrome in alcoholism without amnesia

OBJECTIVES: To test the dysexecutive syndrome (DES) hypothesis of chronic alcoholism by the neuropsychological group and case study approaches. METHODS: A comprehensive neuropsychological assessment, including the "behavioural assessment of dysexecutive syndrome", a battery of tests recently designed to be "ecologically valid", was administered to 17 patients with chronic alcoholism without amnesia to examine executive functions, intelligence, and memory. In terms of each neuropsychological measure, reciprocal analyses of group means and individual case profiles were conducted: for the first contrasting the alcoholic patients with 17 age matched healthy subjects; and for the second making intersubject and intrasubject comparison of the patients, according to percentile basis impairment indices obtained from the control subjects. RESULTS: Despite relatively unimpaired memory and intelligence, the patients as a whole had the impairment of a wide range of executive domains, extending to "everyday" problem solving as well as more elementary aspects of executive functions, such as visuospatial performance, mental set shifting, and the inhibition of habitual behaviour. The profile analysis divided individual patients into four groups: the representative DES characterised by a clear dissociation between impaired executive functions and preserved intelligence and memory; the group of a modified dysexecutive pattern in which memory as well as executive functions were impaired with intelligence preserved; the group of general cognitive deterioration; and the group of unimpaired cognitive functioning. About two thirds of the patients were categorised into either the first or the second type of DES. CONCLUSION: DES characterised by the even more pronounced impairment of executive functions than of intelligence and memory afflicts a considerable proportion of patients with chronic alcoholism. Due to its subtlety, this would be potentially left out, unless appropriate behavioural measures were administered. This condition may prevent patients with alcoholism from achieving full recovery and benefiting from rehabilitation.     

Acute basal ganglia infarcts in poststroke fatigue: an MRI study

Lesions located in the basal ganglia (BG) are thought to be involved in the fatigue observed in neurological disorders. However, the significance of the location of infarcts in poststroke fatigue (PSF) is unknown. This study examined the association between BG infarcts and PSF. A total of 334 Chinese patients with acute ischemic stroke consecutively admitted to the acute stroke unit of a university-affiliated regional hospital in Hong Kong participated in the study. At admission, a host of demographic and clinical characteristics was collected and the number and location of acute infarcts were evaluated with MRI. All participants were assessed for PSF with the fatigue severity scale (FSS) 3 months after their index stroke. PSF was defined as a mean FSS score of 4.0 or more. Depressive symptoms were measured by the geriatric depression scale (GDS). Seventy-eight (23.4%) patients had PSF. In the univariate analysis, the PSF group included more females, had higher GDS scores, and a higher number of acute infarcts, and the PSF patients were more likely to have acute infarcts at the BG. Acute BG infarct remained an independent predictor of PSF in the multivariate analysis. In conclusion, these results suggest that BG infarcts may play a role in the development of PSF.     

Association between apathy/depression and executive function in patients with Alzheimer's disease

ABSTRACTBackground: Apathy and depression may be strongly associated with executive dysfunction in Alzheimer's disease (AD). The Frontal Assessment Battery (FAB) is an instrument for assessing executive function. The dual task paradigm is also useful for assessing divided attention. However, the association between apathy/depression and these tasks is unclear.Methods: Both the FAB and the dual task were used to evaluate AD patients. A two-way analysis of variance was then conducted between the FAB and dual task results and the absence versus the presence of depression or the absence versus the presence of apathy.Results: Of 88 patients with AD, 26 had both apathy and depression, 26 had depression only, 18 had apathy only, and 18 had neither. Total FAB scores and dual task scores differed significantly between the AD patients with depression and those without depression; the scores were also different between those with apathy and those without apathy. Also, a significant interaction between depression and apathy was noted for the total FAB and dual task scores.Conclusions: The deficits in the total FAB and dual task scores were larger in AD patients with both apathy and depression compared with patients with either apathy or depression alone. AD patients with both symptoms may have greater deficits in frontal lobe function relative to AD patients with either apathy or depression alone.     

The role of executive functioning in spontaneous confabulation.

OBJECTIVE: To follow the recovery course of a patient who exhibited an amnesic-confabulatory syndrome in conjunction with severe executive dysfunction in the first week following bithalamic infarction. BACKGROUND: Previous studies have shown that spontaneous confabulation originates from the combination of amnesia and executive dysfunction and that the degree of confabulation is determined by the degree of executive dysfunction. However, a few studies have also reported a dissociation between spontaneous confabulation and executive dysfunction. Therefore, the role of executive functioning in spontaneous confabulation is presently unclear. METHOD: Clinical examinations, magnetic resonance imaging (MRI), and cognitive and behavioral assessments with a focus on executive functions were conducted within the first week poststroke and after 6 months. RESULTS: MRI showed a bithalamic infarction involving the territory of the paramedian arteries predominantly affecting the dorsomedial and intralaminar nuclei of the thalami. Disappearance of spontaneous confabulation paralleled a specific recovery in mental flexibility, whereas all other executive components and long-term memory remained severely impaired at 6 months poststroke. CONCLUSIONS: Our case study provides additional evidence that mental flexibility, but not executive functioning in general, is a prerequisite for spontaneous confabulation. Direct or indirect functional deactivation of dorsolateral prefrontal cortex may be necessary for the development of spontaneous confabulation.     

Executive functioning in depressed patients with suicidal ideation

OBJECTIVE: Suicidal thinking has been associated with cognitive rigidity, however, not all depressed patients contemplate suicide. Therefore, we hypothesized that compared with depressed subjects without suicidal ideation, depressed individuals with suicidal ideation would display poorer performance on measures of executive functioning that involve mental flexibility. METHOD: In-patients with a current major depressive episode who had no current suicidal ideation (n=28) were compared with those who had current suicidal ideation (n=5) on measures of executive functioning and two neurocognitive tests that predominantly assess non-frontal regions. RESULTS: Compared with non-suicidal depressed patients, depressed suicidal patients performed significantly worse on several measures of executive functioning after controlling for age, IQ, severity of depression and prior suicide attempts. The two groups performed similarly on tests that predominantly assess non-frontal regions. CONCLUSION: Depressed individuals contemplating suicide have cognitive rigidity, which does not appear to be a global brain dysfunction. Suicidal mental states may result from dysfunctional executive decision-making that is associated with the frontal lobe.     

A two year longitudinal study of poststroke mood disorders: prognostic factors related to one and two year outcome

In a prospective study of mood disorders in 103 stroke patients, we examined the predictive value of affective, cognitive, social and neurologic variables obtained in-hospital and at six months poststroke in terms of outcome as determined by the same measures at one and two years follow-up. The following factors were found to have prognostic significance: 1) Lesion Location: proximity of the lesion on CT scan to the frontal pole in patients with left anterior infarcts showed a strong positive relationship with severity of depression at one year but not at two years poststroke. 2) Affective Status: depression (in-hospital and at 6 months) strongly predicted depression at one year but not at two years poststroke. Additionally, in-hospital depression significantly correlated with physical impairment at two years, while depression at six months bore a moderate relationship to physical impairment at one year. 3) Physical Impairment: impairment in activities of daily living in-hospital bore a modest relationship to depression at one year while such impairment at six months correlated strongly with depression at both one and two years. These findings may reflect the natural course of major depression which remits between one and two years poststroke. Although stroke lesion location is the strongest predictor of subsequent depression, there appears to be a reciprocal relationship between physical impairment and depression (i.e., depression predicts impairment and impairment predicts depression). Since poststroke depressions are amenable to therapeutic intervention, these prognostic factors may have implications for the treatment and rehabilitation of stroke patients.     

Prevention and treatment of poststroke depression with mirtazapine in patients with acute stroke

BACKGROUND AND OBJECTIVE: Poststroke depression is one of the most frequent complications of stroke, affecting approximately 20% to 40% of all patients. In spite of the importance of this neuropsychiatric disorder, little attention has been given to the prevention of poststroke depression. The purpose of this study was to examine whether prophylactic treatment with the antidepressant mirtazapine in patients with acute stroke given from day 1 after the incidence prevents poststroke depression. METHOD: Patients with ischemic stroke received either 30 mg mirtazapine or no antidepressant medication from day 1 after the stroke in an open, randomized study design. Data were collected from August 2001 to December 2002. Seventy patients were enrolled in the study and were reexamined on days 7, 44, 90, 180, 270, and 360 using neurologic, functional, and depression rating scales. Those poststroke patients who developed depression (DSM-IV criteria) but had been randomly assigned to the nontreatment group were given the antidepressant mirtazapine after the diagnosis of depression had been established. RESULTS: Forty percent (14/35) of the nontreated patients and only 5.7% (2/35) of the patients who were treated with mirtazapine developed poststroke depression. Altogether, 16 patients developed poststroke depression, 15 of whom remitted after initiation of treatment with mirtazapine. CONCLUSION: Mirtazapine significantly reduced the rate of poststroke depression in patients with acute stroke. The study also demonstrated that this antidepressant was highly effective in treating poststroke depression.