Impaired context reversal learning, but not cue reversal learning, in patients with amnestic mild cognitive impairment

It has been proposed that reversal learning is impaired following damage to the orbitofrontal and ventromedial frontal cortex (OFC/VMFC) and to the medial temporal lobe (MTL), including the hippocampal formation. However, the exact characteristics of the MTL-associated reversal learning deficit are not known. To investigate this issue, we assessed 30 newly diagnosed patients with amnestic mild cognitive impairment (aMCI) and 30 matched healthy controls. All patients fulfilled the aMCI criteria of the Mayo Clinic Alzheimer's Disease Research Center and underwent head magnetic resonance imaging that confirmed MTL atrophy. Reversal learning was assessed using a novel reinforcement learning task. Participants first acquired and then reversed stimulus-outcome associations based on negative and positive feedback (losing and gaining points). Stimuli consisted of a cue (geometric shapes) and a spatial context (background color or pattern). Neuropsychological assessment included tasks related to the MTL (paired associates learning), dorsolateral prefrontal cortex (DLPFC) (extradimensional shift, One-touch Stockings of Cambridge), and OFC/VMFC (Holiday Apartment Task). Results revealed that, relative to controls, patients with aMCI exhibited a marked reversal learning deficit, which was highly selective for the reversal of context. The acquisition of stimulus-outcome associations and cue reversal learning were spared. Performance on the context reversal learning task significantly correlated with the right hippocampal volume. In addition, patients with aMCI had deficits on tests related to DLPFC but not to OFC/VMFC. However, DLPFC dysfunctions were not associated with context reversal learning. These results suggest that MTL deficits in aMCI selectively affect context reversal learning when OFC/VMFC functions are spared. This deficit is not influenced by the valence of the outcome (positive or negative feedback) and by executive dysfunctions.     

Delayed response tasks and prefrontal lesions in man—Evidence for self generated patterns of behaviour with poor environmental modulation

The functions of the frontal lobes in humans are still under debate, mainly because none of the neuropsychological tests used for their assessment is sufficiently specific for frontal dysfunction. In animals, the delayed reaction paradigm is considered to be a specific marker of the function of dorsolateral region of the prefrontal cortex. It seemed of interest, therefore, to attempt to apply this paradigm to patients with recent and limited cortical lesion of vascular origin. The performance of patients with dorsolateral prefrontal lesion (n = 10) was compared to that of patients with post-central lesion (n = 10) and control subjects (n = 24), in four experiments: a Delayed Response task in which the correct answer was previously indicated by an explicit cue (externally guided task); Delayed Alternation and Non-Alternation tasks coupled with a Delayed Reversal task in which the patient had to discover the rule by himself in the absence of explicit cues (internally driven tasks).

Patients with prefrontal lesion showed a specific deficit in the Delayed Response task, the emergence of a stereotyped behaviour in the Delayed Alternation task and an inability to deduce and to transfer rules (non-alternation and reversal), mainly because of difficulty in abandoning previous behaviours. Our study demonstrates that the prefrontal cortex plays a role in behavioural adaptation to challenging new situations by inhibiting not only ongoing elaborated programmes but also the emergence of previously established automatic programmes. The respective role of the prefrontal cortex and the basal ganglia in these two levels of behavioural organization is discussed.     

Frontal lobe involvement in spatial span: converging studies of normal and impaired function

Although monkey lesion studies involving the prefrontal cortex commonly report working memory deficits, and neuroimaging studies consistently show prefrontal involvement in such tasks, patients with damage to this region commonly fail to show any working memory impairment. Such a discrepancy may be due to insensitive testing measures for patients, as well as small, yet critical differences between working memory tasks in imaging and patient studies. The current study utilised a more sensitive measure of spatial working memory spans, based either on structured or unstructured spatial arrays. A PET study in normal subjects confirmed that both variants did indeed activate prefrontal cortex. The same tasks were given to frontal lobe patients and closely matched controls. Patients with large frontal lesions were significantly impaired on this task, with those patients with damage to the right dorsolateral prefrontal cortex appearing particularly impaired. This result demonstrates that prefrontal cortex is necessary for normal working memory, even in simple tasks, such as spatial span. It is suggested, however, that the patient deficit reflects strategic or goal-based dysfunction, rather than storage limitations.     

Lesions of the orbital prefrontal cortex impair the formation of attentional set in rats

In rats, reversal learning impairments are commonly reported after lesions of the orbital prefrontal cortex (OFC), in contrast to the effect of lesions of the medial prefrontal cortex, which impair attentional set-shifting. Comparable dissociations have also been reported in humans, monkeys and mice. However, these two manifestations of behavioural flexibility may share common cognitive processes. The present study tested the hypothesis that lesions of the OFC (an area that integrates expected and actual outcomes to signal which cues in the environment predict reward) would impair the formation of attentional set as well as impairing reversal learning. We compared the performance of lesioned and control rats on two set-shifting tasks. The first task we used, 'the 4ID task', had no reversal stages, but multiple intradimensional acquisitions before the extradimensional shift stage, to assess set-formation as well as set-shifting. The second task was the standard intradimensional/extradimensional '7-stage task', which includes reversal learning stages after each compound acquisition. Compared with controls, lesioned rats were slower to form attentional set on the 4ID task. When they did form a set, they required more trials to complete the extradimensional shift stage. On the 7-stage task, we replicated our previous finding of impaired reversal learning and reduced shift-costs. We interpret these findings as reflecting a single deficit in identifying relevant cues after unexpected outcomes, which supports recent models of OFC function. Our findings challenge the assumption that the contribution of the OFC to behavioural flexibility is limited to reversal learning.     

Dissociable roles of prefrontal subregions in self-ordered working memory performance

The anatomical segregation of executive control processes within the prefrontal cortex remains poorly defined. The present study focused on strategy implementation on two working memory tasks: the CANTAB spatial working memory task and a visuospatial sequence generation task. These measures were administered to a group of frontal lesion patients and a comparison group of healthy subjects. Frontal patients with damage to the right inferior frontal gyrus were impaired on the CANTAB spatial working memory task, compared with healthy controls and patients without damage to this region. This deficit was most strongly related to the pars opercularis subregion (BA44) and was accompanied by poor strategy usage. On the sequence generation task, frontal lesion patients were impaired on a strategy-training phase when the working memory demands of the task were reduced, but had relatively intact performance on other phases of the task. Performance on the training phase was correlated with the amount of damage to the dorsolateral prefrontal cortex (DLPFC: BA46/9). These results support theoretical notions of prefrontal cortical function that emphasise its contribution to executive processes such as mnemonic strategies and monitoring over its role as a short-term memory store. Moreover, we provide evidence for the first time that such functions are dependent on dissociable brain regions within the prefrontal cortex.     

Selective prefrontal serotonin depletion impairs acquisition of a detour-reaching task

We have recently shown that serotonin in the primate orbitofrontal cortex (OFC) contributes to the flexible control of behaviour. 5,7-dihydroxytryptamine-induced 5-HT depletions of OFC impair performance on a serial reversal discrimination task [Clarke et al. (2004)Science, 304, 878-880]. The deficit is characterized by perseverative responding to the previously rewarded stimulus, a deficit similar to that seen following lesions of the intrinsic neurones of the OFC [Dias et al. (1996)Nature, 380, 69-72]. The effect is neurochemically selective as dopaminergic lesions of the OFC, induced by 6-hydroxydopamine, have no effect [Clarke et al. (2006)Cerebral Cortex]. In order to test for the generality of the effect of serotonin on orbitofrontal processing and, in particular, its effects on flexible behaviour, the present study investigated the effects of serotonin depletions of OFC on performance of another task dependent upon an intact OFC, the detour-reaching task [Wallis et al. (2001)European Journal of Neuroscience, 13, 1797-1808]. Successful performance of this task requires inhibition of the animal's prepotent response tendency to reach directly along its line of sight to the reward. Compared with sham-operated controls, we found that lesioned monkeys made significantly more barrier reaches directly along their line of sight to the visible reward during task acquisition. This finding provides further support for the role of prefrontal serotonin in inhibitory control processes specifically in tasks sensitive to OFC dysfunction.     

Orbitofrontal cortex dysfunction in attention-deficit hyperactivity disorder revealed by reversal and extinction tasks

Attention-deficit hyperactivity disorder (ADHD) has been considered a mental illness in which the frontal lobe is dysfunctional. The orbitofrontal cortex (OFC) controls emotional and motivational behaviors which are impaired in ADHD. Patients with OFC damage have shown impaired performance in reversal and extinction tasks in a simple go/no-go paradigm. We assigned ADHD subjects the two tasks to examine a hypothesized dysfunction of OFC. ADHD subjects indeed showed a performance deficit in the tasks, supporting OFC dysfunction in ADHD. Furthermore, a discriminat analysis using the task performance variables correctly classified 89.7% of the participants among ADHD patients and normal controls.     

Visual recognition impairment follows ventromedial but not dorsolateral prefrontal lesions in monkeys

Visual recognition in monkeys appears to involve the participation of two limbothalamic pathways, one including the amygdala and the magnocellular portion of the medial dorsal nucleus (MDmc) and the other, the hippocampus and the anterior nuclei of the thalamus (Ant N). Both MDmc and Ant N project, in turn, to the prefrontal cortex, mainly to its ventral and medial portions. To test whether the prefrontal projection targets of the two limbothalamic pathways also participate in memory functions, performance on a variety of learning and memory tasks was assessed in monkeys with lesions of the ventromedial prefrontal cortex (Group VM). Normal monkeys and monkeys with lesions of dorsolateral prefrontal cortex (Group DL) served as controls. Group VM was severely impaired on a test of object recognition, whereas Group DL did not differ appreciably from normal animals. Conversely, the animals in Group VM were able to learn a spatial delayed response task, whereas 2 of the 3 animals in Group DL could not. Neither group was impaired in the acquisition of visual discrimination habits, even though the successive trials on a given discrimination were separated by 24-h intervals. The patterns of deficit suggest that ventromedial prefrontal cortex constitutes another station in the limbothalamic system underlying cognitive memory processes, whereas the dorsolateral prefrontal cortex lies outside this system. The results support the view that the classical delayed-response deficit observed after dorsolateral prefrontal lesions represents a perceptuo-mnemonic impairment in spatial functions selectively rather than a memory loss of a more general nature.     

Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.

OBJECTIVE: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. METHOD: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task. RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. CONCLUSIONS: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.     

Reward-related reversal learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in humans

Neurophysiological studies in primates and neuroimaging studies in humans suggest that the orbito-frontal cortex is involved in representing the reward value of stimuli and in the rapid learning and relearning of associations between visual stimuli and rewarding or punishing outcomes. In the present study, we tested patients with circumscribed surgical lesions in different regions of the frontal lobe on a new visual discrimination reversal test, which, in an fMRI study (O'Doherty, Kringelbach, Rolls, Hornak, & Andrews, 2001), produced bilateral orbito-frontal cortex activation in normal subjects. In this task, touching one of two simultaneously presented patterns produced reward or loss of imaginary money delivered on a probabilistic basis to minimize the usefulness of verbal strategies. A number of types of feedback were present on the screen. The main result was that the group of patients with bilateral orbito-frontal cortex lesions were severely impaired at the reversal task, in that they accumulated less money. These patients often failed to switch their choice of stimulus after a large loss and often did switch their choice although they had just received a reward. The investigation showed that bilateral lesions were required for this deficit, since patients with unilateral orbito-frontal cortex (or medial prefrontal cortex) lesions were not impaired in the probabilistic reversal task. The task ruled out a simple motor disinhibition as an explanation of the deficit in the bilateral orbito-frontal cortex patients, in that the patients were required to choose one of two stimuli on each trial. A comparison group of patients with dorsolateral prefrontal cortex lesions was in some cases able to do the task, and in other cases, was impaired. Posttest debriefing showed that all the dorsolateral prefrontal patients who were impaired at the task had failed to pay attention to the crucial feedback provided on the screen after each trial about the amount won or lost on each trial. In contrast, all dorsolateral patients who paid attention to this crucial feedback performed normally on the reversal task. Further, it was confirmed that the bilateral orbito-frontal cortex patients had also paid attention to this crucial feedback, but in contrast had still performed poorly at the task. The results thus show that the orbital prefrontal cortex is required bilaterally for monitoring changes in the reward value of stimuli and using this to guide behavior in the task; whereas the dorsolateral prefrontal cortex, if it produces deficits in the task, does so for reasons related to executive functions, such as the control of attention. Thus, the ability to determine which information is relevant when making a choice of pattern can be disrupted by a dorsolateral lesion on either side, whereas the ability to use this information to guide behavior is not disrupted by a unilateral lesion in either the left or the right orbito-frontal cortex, but is severely impaired by a bilateral lesion in this region. Because both abilities are important in many of the tasks and decisions that arise in the course of daily life, the present results are relevant to understanding the difficulties faced by patients after surgical excisions in different frontal brain regions.     

Double dissociation between hippocampal and prefrontal lesions on an operant delayed matching task and a water maze reference memory task

The hippocampus and prefrontal cortex have both been implicated in various aspects of the acquisition, retention and performance of delayed matching to position (DMTP) tasks in the rat, although their precise respective contributions remain unclear. In the present study, rats were trained preoperatively on DMTP before receiving excitotoxic bilateral lesions of either the entire hippocampus or the medial prefrontal cortex. Rats with lesions of the prefrontal cortex exhibited a significant delay-dependent impairment on retention of the DMTP task, whereas hippocampal lesions were without effect. Rats were also exposed to a switch in the contingencies to a 'non-matching' rule, as an analogue of switching between decision rules in the human Wisconsin Card Sorting Test, in which human patients with prefrontal damage are impaired. Both lesion groups acquired the new contingency at control levels, providing no evidence towards a role for either of these areas in this type of rule-switching. The same rats were also assessed in a spatial reference memory task in the water maze, which revealed an impairment in escape latencies and path length that was specific to the hippocampal lesions. The results corroborate previous evidence that the hippocampus is not necessary for at least some aspects of working memory performance in the DMTP task, whereas the delay-dependent deficit in the prefrontal lesion group support this task as a potentially powerful tool for assessing the cognitive changes associated with frontal damage and repair.     

Schizophrenia patients demonstrate a distinctive pattern of decision-making impairment on the Iowa Gambling Task

Although dorsolateral prefrontal cortex (DLPFC) abnormalities in schizophrenia are well established, several lines of evidence suggest the orbitofrontal cortex (OFC) may also be dysfunctional in this disorder. We examined the performance of schizophrenia patients and nonpatient controls on the Iowa Gambling Task [Cognition 50 (1994) 7], a decision-making task sensitive to OFC damage that involves a series of selections from four decks of cards that vary in their reward/punishment profiles. Patients also completed neuropsychological tests assessing DLPFC functions and clinical symptom assessments. The schizophrenic patients demonstrated a pattern of impaired performance that differed both from healthy controls and from the "non-conservative" pattern typically found in patients with OFC lesions. The patients selected from the two card decks that had low frequency and high magnitude punishments significantly more often than the decks with high frequency and low magnitude punishments. Performance on the task was not strongly related to tests sensitive to DLPFC dysfunction but was correlated with negative symptoms. Results suggest that individuals with schizophrenia display a pattern of compromised decision-making that is somewhat distinct from that found in OFC lesion patients and that may be linked to certain clinical symptoms.     

Pre-surgical training ameliorates orbitofrontal-mediated impairments in spatial reversal learning

We recently reported that orbitofrontal cortical (OFC) lesions impaired reversal learning of an instrumental two-lever spatial discrimination task, a deficit manifested as increased perseveration on the pre-potent response. Here we examine whether exposure to reversal learning test pre-operatively may have a beneficial effect for future reversal learning of OFC-lesioned animals. Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both 'cognitive flexibility' and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, two reversals were introduced. Rats were then matched according to their reversal performance and subjected to bilateral excitotoxic OFC lesions. Following recovery, a series of four reversals was presented. OFC lesions impaired neither retention nor reversal phases. These data, together with the previously reported reversal deficit following OFC lesions, suggest that OFC is not needed when task experience has been gained but it is necessary when task demands are relatively high.     

The effects of frontal lobe lesions on goal achievement in the water jug task.

Patients with prefrontal cortex lesions are impaired on a variety of planning and problem-solving tasks. We examined the problem-solving performance of 27 patients with focal frontal lobe damage on the Water Jug task. The Water Jug task has never been used to assess problem-solving ability in neurologically impaired patients nor in functional neuroimaging studies, despite sharing structural similarities with other tasks sensitive to prefrontal cortex function, including the Tower of Hanoi, Tower of London, and Wisconsin Card Sorting Task (WCST). Our results demonstrate that the Water Jug task invokes a unique combination of problem-solving and planning strategies, allowing a more precise identification of frontal lobe lesion patients' cognitive deficits. All participants (patients and matched controls) appear to be utilizing a hill-climbing strategy that does not require sophisticated planning; however, frontal lobe lesion patients (FLLs) struggled to make required "counterintuitive moves" not predicted by this strategy and found within both solution paths. Left and bilateral FLLs were more impaired than right FLLs. Analysis of the left hemisphere brain regions encompassed by the lesions of these patients found that poor performance was linked to left dorsolateral prefrontal cortex damage. We propose that patients with left dorsolateral prefrontal cortex lesions have difficulty making a decision requiring the conceptual comparison of nonverbal stimuli, manipulation of select representations of potential solutions, and are unable to appropriately inhibit a response in keeping with the final goal.     

Comparison of differential neuronal responsiveness for different regions of the prefrontal cortex in a conditional visual discrimination task

To investigate neuronal processing during monkeys' performance of a visual conditional discrimination task, recordings were made from four areas of prefrontal cortex (ventromedial, orbitofrontal, dorsolateral and anterior cingulate) where lesions have been shown to produce impairment of such tasks. Of 1911 recorded neurons, 573 (31%) responded to elements of the task. This proportion was less than the 50% previously reported as responsive in temporal cortex under the same conditions, suggesting sparser encoding in prefrontal than temporal cortex. Of the responsive prefrontal neurons, 165 (29%) responded differently on the different types of trial, so signalling various types of information relevant to task performance and cognition. In line with recent lesion findings, in the dorsolateral region the incidence of such differentially responsive neurons was only an eighth that in the other regions. The relatively high incidence of neuronal responses that encoded a potential instruction cue rather than specific individual stimulus arrangements was consistent with the animals solving the task by using such information, though other neuronal responses could have enabled the task to have been solved by rote learning. Compared to temporal neurons, prefrontal responses more frequently coded information relating to the planned behavioural response rather than perceptual aspects of the task. Population differential response latencies were long (> approximately 225 ms) in prefrontal cortex. A comparison of such differential latencies between temporal and prefrontal cortex indicated that potential information flow was likely to be primarily from temporal to prefrontal cortex rather than vice versa.     

The neural basis of risk ratings: evidence from a functional magnetic resonance imaging (fMRI) study

Research investigating risk perception suggests that not only the quantitative parameters used in technical risk assessment (i.e., frequency and severity of harm) but also ‘qualitative’ aspects such as the dread a hazard provokes or its controllability influence risk judgments. It remains to be elucidated, however, which neural mechanism underlie risk ratings in healthy subjects. Using fMRI to detect changes in neural activity we compared the neural activations elicited by risk ratings with those elicited by a letter detection task performed on the same stimuli. The latter task served to control for basic stimulus processing, response selection and button-pressing during task performance. Risk ratings differentially activated the medial prefrontal cortex, the inferior frontal gyrus, the cerebellum (P < 0.05, FWE corrected, whole brain approach), and in an additional ROI analysis the amygdala (P < 0.05, FWE corrected). Of these structures, particularly the amygdala and the prefrontal cortex have been previously associated with decisions about affective interference. Furthermore our data suggest both, similarities and differences between the neural correlates of risk ratings and risk taking as involved, for e.g., in gambling tasks.     

Response Selection Deficits in Melancholic but not Nonmelancholic Unipolar Major Depression

One consistent functional imaging finding from patients with major depression has been abnormality of the anterior cingulate cortex (ACC). Hypoperfusion has been most commonly reported, but some studies suggest relative hyperperfusion is associated with response to somatic treatments. Despite these indications of the possible importance of the ACC in depression there have been relatively few cognitive studies ACC function in patients with major depression. The present study employed a series of reaction time (RT) tasks involving selection with melancholic and nonmelancholic depressed patients, as well as age-matched controls. Fifteen patients with unipolar major depression (7 melancholic, 8 nonmelancholic) and 8 healthy age-matched controls performed a series of response selection tasks (choice RT, spatial Stroop, spatial stimulus-response compatibility (SRC), and a combined Stroop + SRC condition). Reaction time and error data were collected. Melancholic patients were significantly slower than controls on all tasks but were slower than nonmelancholic patients only on the Stroop and Stroop + SRC conditions. Nonmelancholic patients did not differ from the control group on any task. The Stroop task seems crucial in differentiating the two depressive groups, they did not differ on the choice RT or SRC tasks. This may reflect differential task demands, the SRC involved symbolic manipulation that might engage the dorsal ACC and dorsolateral prefrontal cortex (DLPFC) to a greater extent than the, primarily inhibitory, Stroop task which may engage the ventral ACC and orbitofrontal cortex (OFC). This might suggest the melancholic group showed a greater ventral ACC-OFC deficit than the nonmelancholic group, while both groups showed similar dorsal ACC-DLPFC deficit.     

Response selection deficits in melancholic but not nonmelancholic unipolar major depression

One consistent functional imaging finding from patients with major depression has been abnormality of the anterior cingulate cortex (ACC). Hypoperfusion has been most commonly reported, but some studies suggest relative hyperperfusion is associated with response to somatic treatments. Despite these indications of the possible importance of the ACC in depression there have been relatively few cognitive studies ACC function in patients with major depression. The present study employed a series of reaction time (RT) tasks involving selection with melancholic and nonmelancholic depressed patients, as well as age-matched controls. Fifteen patients with unipolar major depression (7 melancholic, 8 nonmelancholic) and 8 healthy age-matched controls performed a series of response selection tasks (choice RT, spatial Stroop, spatial stimulus-response compatibility (SRC), and a combined Stroop + SRC condition). Reaction time and error data were collected. Melancholic patients were significantly slower than controls on all tasks but were slower than nonmelancholic patients only on the Stroop and Stroop + SRC conditions. Nonmelancholic patients did not differ from the control group on any task. The Stroop task seems crucial in differentiating the two depressive groups, they did not differ on the choice RT or SRC tasks. This may reflect differential task demands, the SRC involved symbolic manipulation that might engage the dorsal ACC and dorsolateral prefrontal cortex (DLPFC) to a greater extent than the, primarily inhibitory, Stroop task which may engage the ventral ACC and orbitofrontal cortex (OFC). This might suggest the melancholic group showed a greater ventral ACC-OFC deficit than the nonmelancholic group, while both groups showed similar dorsal ACC-DLPFC deficit.     

GABA(A)-receptor mRNA expression in the prefrontal and temporal cortex of ALS patients

There is evidence that excitotoxic cell death is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Electrophysiological and histological studies support the pathophysiological concept of an impaired inhibitory, namely GABAergic, control of the motoneurons in the cerebral cortex of ALS patients. Recently, pathological, neuropsychological and functional imaging data have challenged the view that ALS is a disorder restricted to the motor system. The aim of our study was to investigate the expression of the most abundant GABA_A-receptor subunit mRNAs and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) in the prefrontal, temporal, occipital and cerebellar cortex of ALS patients compared to tissue of control persons. We performed in situ hybridization histochemistry (ISH) on human post-mortem cortex sections of ALS patients (n = 5) and age-matched controls with no history of neurological disease (n = 5).

In the prefrontal and temporal cortex of ALS patients, we detected significantly reduced mRNA expression of the 1-subunit, while the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) was significantly upregulated in these regions. In the occipital and cerebellar cortex, we did not see disease-specific differences of the mRNA expression of the investigated subunits.     

Impaired dimensional selection but intact use of reward feedback during visual discrimination learning in Parkinson's disease

It has been suggested that Parkinson's disease (PD) impairs the ability to learn on the basis of reward or reinforcing feedback i.e., by trial-and-error. In many learning tasks, particular 'dimensions' of stimulus information are relevant whilst others are irrelevant; therefore, efficient performance depends on identifying the dimensions of these 'compound' stimuli and selecting the relevant dimension for further processing. We investigated the ability of patients with PD, as well as patients with Huntington's disease and patients with frontal or temporal lobe lesions, to learn visual discriminations which required either a number of associations to be learned concurrently (the 'eight-pair' task) or the selection of information from compound stimuli (the 'five-dimension' task), both tasks being learned by trial-and-error. None of the basal ganglia disorder patient groups was impaired on the eight-pair task, militating against a crucial role for these brain structures in trial-and-error learning per se. Patients with mild, medicated PD, but not unmedicated PD patients, were impaired at identifying all five feature dimensions in the five-dimension task, implying dopaminergic 'overdosing' of the ability to analyse compound stimuli in terms of their component dimensions. Temporal lobe lesion patients performed similarly, suggesting that the temporal lobe may be the site of the medication overdose effect. Patients with severe, medicated PD were impaired at compound discrimination learning on the five-dimension task in the absence of an underlying impairment in identifying component stimulus dimensions; this pattern resembled that seen in Huntington's disease and frontal lobe lesion patients, implying that fronto-striatal circuitry is involved in the formation of rules based upon selected stimulus dimensions.