Laminar distribution of β-amyloid (Aβ) peptide deposits in the frontal lobe in familial and sporadic Alzheimer's disease

To determine whether genetic factors influence frontal lobe degeneration in Alzheimer's disease (AD), the laminar distributions of diffuse, primitive, and classic β-amyloid (Aβ) peptide deposits were compared in early-onset familial AD (EO-FAD) linked to mutations of the amyloid precursor protein (APP) or presenilin 1 (PSEN1) gene, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The influence of apolipoprotein E (Apo E) genotype on laminar distribution was also studied. In the majority of FAD and SAD cases, maximum density of the diffuse and primitive Aβ deposits occurred in the upper cortical layers, whereas the distribution of the classic Aβ deposits was more variable, either occurring in the lower layers, or a double-peaked (bimodal) distribution was present, density peaks occurring in upper and lower layers. The cortical layer at which maximum density of Aβ deposits occurred and maximum density were similar in EO-FAD, LO-FAD and SAD. In addition, there were no significant differences in distributions in cases expressing Apo E ε4 alleles compared with cases expressing the ε2 or ε3 alleles. These results suggest that gene expression had relatively little effect on the laminar distribution of Aβ deposits in the frontal lobe of the AD cases studied. Hence, the pattern of frontal lobe degeneration in AD is similar regardless of whether it is associated with APP and PSEN1, mutation, allelic variation in Apo E, or with SAD.

Myoinositol Abnormalities in Temporal Lobe Epilepsy

Purpose: This study used magnetic resonance spectroscopy (MRS) to examine metabolite abnormalities in the temporal and frontal lobe of patients with temporal lobe epilepsy (TLE) of differing severity. Methods: We investigated myoinositol in TLE by using short-echo MRS in 34 TLE patients [26 late onset (LO-TLE), eight hippocampal sclerosis (HS-TLE)], and 16 controls. Single-voxel short-echo (35 ms) MR spectra of temporal and frontal lobes were acquired at 1.5 T and analyzed by using LCModel. Results: The temporal lobe ipsilateral to seizure origin in HS-TLE, but not LO-TLE, had reduced N-acetylaspartate (NA) and elevated myoinositol (MI; HS-TLE NA, 7.8 ± 1.9 mM, control NA, 9.2 ± 1.3 mM; p < 0.05; HS-TLE MI, 6.1 ± 1.6 mM, control mI 4.9 ± 0.8 mM, p< 0.05). Frontal lobe MI was low in both patient groups (LO-TLE, 4.3 ± 0.8 mM; p < 0.05; HS-TLE, 3.6 ±.05 mM; p < 0.001; controls, 4.8 ± 0.5 mM). Ipsilateral frontal lobes had lower MI (3.8 ± 0.7 mM; p < 0.01) than contralateral frontal lobes (4.3 ± 0.8 mM; p < 0.05). Conclusions: MI changes may distinguish between the seizure focus, where MI is increased, and areas of seizure spread where MI is decreased.

Disentangling the cognitive components supporting Austin Maze performance in left versus right temporal lobe epilepsy

Neuropsychological tests requiring patients to find a path through a maze can be used to assess visuospatial memory performance in temporal lobe pathology, particularly in the hippocampus. Alternatively, they have been used as a task sensitive to executive function in patients with frontal lobe damage. We measured performance on the Austin Maze in patients with unilateral left and right temporal lobe epilepsy (TLE), with and without hippocampal sclerosis, compared to healthy controls. Performance was correlated with a number of other neuropsychological tests to identify the cognitive components that may be associated with poor Austin Maze performance. Patients with right TLE were significantly impaired on the Austin Maze task relative to patients with left TLE and controls, and error scores correlated with their performance on the Block Design task. The performance of patients with left TLE was also impaired relative to controls; however, errors correlated with performance on tests of executive function and delayed recall. The presence of hippocampal sclerosis did not have an impact on maze performance. A discriminant function analysis indicated that the Austin Maze alone correctly classified 73.5% of patients as having right TLE. In summary, impaired performance on the Austin Maze task is more suggestive of right than left TLE; however, impaired performance on this visuospatial task does not necessarily involve the hippocampus. The relationship of the Austin Maze task with other neuropsychological tests suggests that differential cognitive components may underlie performance decrements in right versus left TLE.

Co-activation of the amygdala, hippocampus and inferior frontal gyrus during autobiographical memory retrieval.

Functional MRI was used to investigate the role of medial temporal lobe and inferior frontal lobe regions in autobiographical recall. Prior to scanning, participants generated cue words for 50 autobiographical memories and rated their phenomenological properties using our autobiographical memory questionnaire (AMQ). During scanning, the cue words were presented and participants pressed a button when they retrieved the associated memory. The autobiographical retrieval task was interleaved in an event-related design with a semantic retrieval task (category generation). Region-of-interest analyses showed greater activation of the amygdala, hippocampus, and right inferior frontal gyrus during autobiographical retrieval relative to semantic retrieval. In addition, the left inferior frontal gyrus showed a more prolonged duration of activation in the semantic retrieval condition. A targeted correlational analysis revealed pronounced functional connectivity among the amygdala, hippocampus, and right inferior frontal gyrus during autobiographical retrieval but not during semantic retrieval. These results support theories of autobiographical memory that hypothesize co-activation of frontotemporal areas during recollection of episodes from the personal past.

Frontal-striatal circuits in cognitive aging: Evidence for caudate involvement

Changes in cognition with aging have been claimed to be due in large part to a decline in frontal lobe function. However, at our present state of knowledge, the emphasis on the frontal lobes to the exclusion of the rest of the frontal-striatal circuits of which they are a part is unwarranted. To argue this point, I consider another anatomical candidate within these circuits, the caudate. Evidence is presented that the caudate decreases in size with age as much as the frontal lobes and that damage to either the frontal lobes or the caudate is accompanied by declines in inhibitory processes, executive control, and cognitive speed similar to those seen in normal aging. Separating the unique contributions of the frontal lobes and the caudate to these circuits is difficult but should be the focus of future studies of the biological basis of cognitive aging.

Frontal eye field neurons assess visual stability across saccades.

The image on the retina may move because the eyes move, or because something in the visual scene moves. The brain is not fooled by this ambiguity. Even as we make saccades, we are able to detect whether visual objects remain stable or move. Here we test whether this ability to assess visual stability across saccades is present at the single-neuron level in the frontal eye field (FEF), an area that receives both visual input and information about imminent saccades. Our hypothesis was that neurons in the FEF report whether a visual stimulus remains stable or moves as a saccade is made. Monkeys made saccades in the presence of a visual stimulus outside of the receptive field. In some trials, the stimulus remained stable, but in other trials, it moved during the saccade. In every trial, the stimulus occupied the center of the receptive field after the saccade, thus evoking a reafferent visual response. We found that many FEF neurons signaled, in the strength and timing of their reafferent response, whether the stimulus had remained stable or moved. Reafferent responses were tuned for the amount of stimulus translation, and, in accordance with human psychophysics, tuning was better (more prevalent, stronger, and quicker) for stimuli that moved perpendicular, rather than parallel, to the saccade. Tuning was sometimes present as well for nonspatial transaccadic changes (in color, size, or both). Our results indicate that FEF neurons evaluate visual stability during saccades and may be general purpose detectors of transaccadic visual change.

Neuronal correlates of metacognition in primate frontal cortex.

Humans are metacognitive: they monitor and control their cognition. Our hypothesis was that neuronal correlates of metacognition reside in the same brain areas responsible for cognition, including frontal cortex. Recent work demonstrated that nonhuman primates are capable of metacognition, so we recorded from single neurons in the frontal eye field, dorsolateral prefrontal cortex, and supplementary eye field of monkeys (Macaca mulatta) that performed a metacognitive visual-oculomotor task. The animals made a decision and reported it with a saccade, but received no immediate reward or feedback. Instead, they had to monitor their decision and bet whether it was correct. Activity was correlated with decisions and bets in all three brain areas, but putative metacognitive activity that linked decisions to appropriate bets occurred exclusively in the SEF. Our results offer a survey of neuronal correlates of metacognition and implicate the SEF in linking cognitive functions over short periods of time.

Influence of the thalamus on spatial visual processing in frontal cortex.

Each of our movements activates our own sensory receptors, and therefore keeping track of self-movement is a necessary part of analysing sensory input. One way in which the brain keeps track of self-movement is by monitoring an internal copy, or corollary discharge, of motor commands. This concept could explain why we perceive a stable visual world despite our frequent quick, or saccadic, eye movements: corollary discharge about each saccade would permit the visual system to ignore saccade-induced visual changes. The critical missing link has been the connection between corollary discharge and visual processing. Here we show that such a link is formed by a corollary discharge from the thalamus that targets the frontal cortex. In the thalamus, neurons in the mediodorsal nucleus relay a corollary discharge of saccades from the midbrain superior colliculus to the cortical frontal eye field. In the frontal eye field, neurons use corollary discharge to shift their visual receptive fields spatially before saccades. We tested the hypothesis that these two components-a pathway for corollary discharge and neurons with shifting receptive fields-form a circuit in which the corollary discharge drives the shift. First we showed that the known spatial and temporal properties of the corollary discharge predict the dynamic changes in spatial visual processing of cortical neurons when saccades are made. Then we moved from this correlation to causation by isolating single cortical neurons and showing that their spatial visual processing is impaired when corollary discharge from the thalamus is interrupted. Thus the visual processing of frontal neurons is spatiotemporally matched with, and functionally dependent on, corollary discharge input from the thalamus. These experiments establish the first link between corollary discharge and visual processing, delineate a brain circuit that is well suited for mediating visual stability, and provide a framework for studying corollary discharge in other sensory systems.

What the brain stem tells the frontal cortex. II. Role of the SC-MD-FEF pathway in corollary discharge.

One way we keep track of our movements is by monitoring corollary discharges or internal copies of movement commands. This study tested a hypothesis that the pathway from superior colliculus (SC) to mediodorsal thalamus (MD) to frontal eye field (FEF) carries a corollary discharge about saccades made into the contralateral visual field. We inactivated the MD relay node with muscimol in monkeys and measured corollary discharge deficits using a double-step task: two sequential saccades were made to the locations of briefly flashed targets. To make second saccades correctly, monkeys had to internally monitor their first saccades; therefore deficits in the corollary discharge representation of first saccades should disrupt second saccades. We found, first, that monkeys seemed to misjudge the amplitudes of their first saccades; this was revealed by systematic shifts in second saccade end points. Thus corollary discharge accuracy was impaired. Second, monkeys were less able to detect trial-by-trial variations in their first saccades; this was revealed by reduced compensatory changes in second saccade angles. Thus corollary discharge precision also was impaired. Both deficits occurred only when first saccades went into the contralateral visual field. Single-saccade generation was unaffected. Additional deficits occurred in reaction time and overall performance, but these were bilateral. We conclude that the SC-MD-FEF pathway conveys a corollary discharge used for coordinating sequential saccades and possibly for stabilizing vision across saccades. This pathway is the first elucidated in what may be a multilevel chain of corollary discharge circuits extending from the extraocular motoneurons up into cerebral cortex.

Connectivity-based parcellation of the human frontal polar cortex

The frontal pole corresponds to Brodmann area (BA) 10, the largest single architectonic area in the human frontal lobe. Generally, BA10 is thought to contain two or three subregions that subserve broad functions such as multitasking, social cognition, attention, and episodic memory. However, there is a substantial debate about the functional and structural heterogeneity of this large frontal region. Previous connectivity-based parcellation studies have identified two or three subregions in the human frontal pole. Here, we used diffusion tensor imaging to assess structural connectivity of BA10 in 35 healthy subjects and delineated subregions based on this connectivity. This allowed us to determine the correspondence of structurally based subregions with the scheme previously defined functionally. Three subregions could be defined in each subject. However, these three subregions were not spatially consistent between subjects. Therefore, we accepted a solution with two subregions that encompassed the lateral and medial frontal pole. We then examined resting-state functional connectivity of the two subregions and found significant differences between their connectivities. The medial cluster was connected to nodes of the default-mode network, which is implicated in internally focused, self-related thought, and social cognition. The lateral cluster was connected to nodes of the executive control network, associated with directed attention and working memory. These findings support the concept that there are two major anatomical subregions of the frontal pole related to differences in functional connectivity.

Frontal networks in adults with autism spectrum disorder

It has been postulated that autism spectrum disorder is underpinned by an ‘atypical connectivity’ involving higher-order association brain regions. To test this hypothesis in a large cohort of adults with autism spectrum disorder we compared the white matter networks of 61 adult males with autism spectrum disorder and 61 neurotypical controls, using two complementary approaches to diffusion tensor magnetic resonance imaging. First, we applied tract-based spatial statistics, a ‘whole brain’ non-hypothesis driven method, to identify differences in white matter networks in adults with autism spectrum disorder. Following this we used a tract-specific analysis, based on tractography, to carry out a more detailed analysis of individual tracts identified by tract-based spatial statistics. Finally, within the autism spectrum disorder group, we studied the relationship between diffusion measures and autistic symptom severity. Tract-based spatial statistics revealed that autism spectrum disorder was associated with significantly reduced fractional anisotropy in regions that included frontal lobe pathways. Tractography analysis of these specific pathways showed increased mean and perpendicular diffusivity, and reduced number of streamlines in the anterior and long segments of the arcuate fasciculus, cingulum and uncinate—predominantly in the left hemisphere. Abnormalities were also evident in the anterior portions of the corpus callosum connecting left and right frontal lobes. The degree of microstructural alteration of the arcuate and uncinate fasciculi was associated with severity of symptoms in language and social reciprocity in childhood. Our results indicated that autism spectrum disorder is a developmental condition associated with abnormal connectivity of the frontal lobes. Furthermore our findings showed that male adults with autism spectrum disorder have regional differences in brain anatomy, which correlate with specific aspects of autistic symptoms. Overall these results suggest that autism spectrum disorder is a condition linked to aberrant developmental trajectories of the frontal networks that persist in adult life.

Depression in temporal lobe epilepsy surgery patients : an FDG-PET study

Summary: Purpose: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery.

Methods: We studied 23 medically refractory TLE patients who underwent anterior temporal lobectomy and who had preoperative FDG-PET scanning. All patients had pre- and postoperative psychiatric assessment. By using statistical parametric mapping (SPM-99), patterns of hypometabolism were compared between patients who had a preoperative history of depression (n = 9) versus those who did not (n = 14) and between those in whom postoperative depression developed (n = 13) versus those in whom it did not (n = 10). A significant region of hypometabolism was set at p < 0.001 for a cluster of ≥20 contiguous voxels.

Results: Patients with a history of depression at any time preoperatively showed focal hypometabolism in ipsilateral orbitofrontal cortex compared with those who did not (t= 4.64; p < 0.001). Patients in whom depression developed postoperatively also showed hypometabolism in the ipsilateral orbitofrontal region (t= 5.10; p < 0.001).

Conclusions: Although this study is methodologically limited, and other explanations merit consideration, orbitofrontal cortex dysfunction, already implicated in the pathophysiology of nonepileptic depression, may also be relevant to the depression of TLE and temporal lobectomy.

Multimodal exercise intervention improves frontal cognitive functions and gait in Alzheimer's disease: A controlled trial

Aim: The objective of the present study was to investigate the effect of a multimodal exercise intervention on frontal cognitive functions and kinematic gait parameters in patients with Alzheimer's disease. Methods: A sample of elderly patients with Alzheimer's disease (n=27) were assigned to a training group (n=14; aged 78.0±7.3years) and a control group (n=13; aged 77.1±7.4years). Multimodal exercise intervention includes motor activities and cognitive tasks simultaneously. The participants attended a 1-h session three times a week for 16weeks, and the control participants maintained their regular daily activities during the same period. The frontal cognitive functions were evaluated using the Frontal Assessment Battery, the Clock Drawing Test and the Symbol Search Subtest. The kinematic parameters of gait-cadence, stride length and stride speed were analyzed under two conditions: (i) free gait (single task); and (ii) gait with frontal cognitive task (walking and counting down from 20 - dual task). Results and discussion: The patients in the intervention group significantly increased the scores in frontal cognitive variables, Frontal Assessment Battery (P<0.001) and Symbol Search Subtest (P<0.001) after the 16-week period. The control group decreased the scores in the Clock Drawing Test (P=0.001) and increased the number of counting errors during the dual task (P=0.008) after the same period. Conclusion: The multimodal exercise intervention improved the frontal cognitive functions in patients with Alzheimer's disease. © 2012 Japan Geriatrics Society.

Frontal assessment battery in a Brazilian sample of healthy controls: normative data

Objective: To show data on the performance of healthy subjects in the Frontal Assessment Battery (FAB), correlating with gender, age, education, and scores in the Mini-Mental State Examination (MMSE). Methods: Two hundred and seventy-five healthy individuals with mean age of 66.4 +/- 10.6 years-old were evaluated. Mean total FAB scores were established according to the educational level. Results: Mean total FAB scores according to the educational level were 10.9 +/- 2.3, for one to three years; 12.8 +/- 2.7, for four to seven years; 13.8 +/- 2.2, for eight to 11 years; and 15.3 +/- 2.3, for 12 or more years. Total FAB scores correlated significantly with education (r=0.47; p<0.0001) and MMSE scores (r=0.39; p<0.0001). No correlation emerged between FAB scores, age, and gender. Conclusion: In this group of healthy subjects, the Brazilian version of the FAB proved to be influenced by the education level, but not by age and gender.

Interference with gesture production by theta burst stimulation over left inferior frontal cortex

The traditional view of a predominant inferior parietal representation of gestures has been recently challenged by neuroimaging studies demonstrating that gesture production and discrimination may critically depend on inferior frontal lobe function. The aim of the present work was therefore to investigate the effect of transient disruption of these brain sites by continuous theta burst stimulation (cTBS) on gesture production and recognition.