Increased segregation of structural brain networks underpins enhanced broad cognitive abilities of cognitive training.

A major challenge in the cognitive training field is inducing broad, far-transfer training effects. Thus far, little is known about the neural mechanisms underlying broad training effects. Here, we tested a set of competitive hypotheses regarding the role of brain integration versus segregation underlying the broad training effect. We retrospectively analyzed data from a randomized controlled trial comparing neurocognitive effects of vision-based speed of processing training (VSOP) and an active control consisting of mental leisure activities (MLA) in older adults with MCI. We classified a subset of participants in the VSOP as learners, who showed improvement in executive function and episodic memory. The other participants in the VSOP (i.e., VSOP non-learners) and a subset of participants in the MLA (i.e., MLA non-learners) served as controls. Structural brain networks were constructed from diffusion tensor imaging. Clustering coefficients (CCs) and characteristic path lengths were computed as measures of segregation and integration, respectively. Learners showed significantly greater global CCs after intervention than controls. Nodal CCs were selectively enhanced in cingulate cortex, parietal regions, striatum, and thalamus. Among VSOP learners, those with more severe baseline neurodegeneration had greater improvement in segregation after training. Our findings suggest broad training effects are related to enhanced segregation in selective brain networks, providing insight into cognitive training related neuroplasticity.

Effects of amnesia on processing in the hippocampus and default mode network during a naturalistic memory task: A case study.

Despite their severely impaired episodic memory, individuals with amnesia are able to comprehend ongoing events. Online representations of a current event are thought to be supported by a network of regions centred on the posterior midline cortex (PMC). By contrast, episodic memory is widely believed to be supported by interactions between the hippocampus and these cortical regions. In this MRI study, we investigated the encoding and retrieval of real life-like events (video clips) in a patient with severe amnesia likely resulting from a stroke to the right (and possibly the left) thalamus, and a group of 20 age-matched controls. Structural MRI revealed grey matter reductions in left hippocampus and left thalamus in comparison to controls. We first characterised the regions activated in the controls while they watched and retrieved the videos. There were no differences in activation between the patient and controls in any of the regions. We then identified a widespread network of brain regions, including the hippocampus, that were functionally connected with the PMC in controls. However, in the patient there was a specific reduction in functional connectivity between the PMC and a region of left hippocampus when both watching and attempting to retrieve the videos. A follow up analysis of the control group revealed that, when watching the videos, the functional connectivity between these two regions was correlated with memory performance. Taken together, these findings support the view that the interactions between the PMC and the hippocampus enable the encoding and retrieval of naturalistic events.

Mammillothalamic Disconnection Alters Hippocampocortical Oscillatory Activity and Microstructure: Implications for Diencephalic Amnesia.

Diencephalic amnesia can be as debilitating as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. Across four cohorts of male rats, we used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampocortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting an important role for the mammillary bodies in the coordination of hippocampocortical activity.SIGNIFICANCE STATEMENT Information flow within the Papez circuit is critical to memory. Damage to ascending mammillothalamic projections has consistently been linked to amnesia in humans and spatial memory deficits in animal models. Here we report on the changes in hippocampocortical oscillatory dynamics that result from chronic lesions of the mammillothalamic tract and demonstrate, for the first time, that the mammillary bodies, independently of the supramammillary region, contribute to frequency modulation of hippocampocortical theta oscillations. Consistent with the associations between oscillatory activity and plasticity, the lesions also result in a suppression of learning-induced plasticity. Together, these data support new functional models whereby mammillary bodies are important for coordinating hippocampocortical activity rather than simply being a relay of hippocampal information as previously assumed.

Patients with hippocampal amnesia successfully integrate gesture and speech.

During conversation, people integrate information from co-speech hand gestures with information in spoken language. For example, after hearing the sentence, "A piece of the log flew up and hit Carl in the face" while viewing a gesture directed at the nose, people tend to later report that the log hit Carl in the nose (information only in gesture) rather than in the face (information in speech). The cognitive and neural mechanisms that support the integration of gesture with speech are unclear. One possibility is that the hippocampus - known for its role in relational memory and information integration - is necessary for integrating gesture and speech. To test this possibility, we examined how patients with hippocampal amnesia and healthy and brain-damaged comparison participants express information from gesture in a narrative retelling task. Participants watched videos of an experimenter telling narratives that included hand gestures that contained supplementary information. Participants were asked to retell the narratives and their spoken retellings were assessed for the presence of information from gesture. For features that had been accompanied by supplementary gesture, patients with amnesia retold fewer of these features overall and fewer retellings that matched the speech from the narrative. Yet their retellings included features that contained information that had been present uniquely in gesture in amounts that were not reliably different from comparison groups. Thus, a functioning hippocampus is not necessary for gesture-speech integration over short timescales. Providing unique information in gesture may enhance communication for individuals with declarative memory impairment, possibly via non-declarative memory mechanisms.

A voxel-based analysis of FDG-PET in traumatic brain injury: regional metabolism and relationship between the thalamus and cortical areas.

The objective was to study the correlations and the differences in glucose metabolism between the thalamus and cortical structures in a sample of severe traumatic brain injury (TBI) patients with different neurological outcomes. We studied 49 patients who had suffered a severe TBI and 10 healthy control subjects using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). The patients were divided into three groups: a vegetative or minimally-conscious state (MCS&VS) group (n=17), which included patients who were in a vegetative or a minimally conscious state; an In-post-traumatic amnesia (In-PTA) group (n=12), which included patients in PTA; and an Out-PTA group (n=20), which included patients who had recovered from PTA. SPM5 software was used to determine the metabolic differences between the groups. FDG-PET images were normalized and four regions of interest were generated around the thalamus, precuneus, and the frontal and temporal lobes. The groups were parameterized using Student's t-test. Principal component analysis was used to obtain an intensity-estimated-value per subject to correlate the function between the structures. Differences in glucose metabolism in all structures were related to the neurological outcome, and the most severe patients showed the most severe hypometabolism. We also found a significant correlation between the cortico-thalamo-cortical metabolism in all groups. Voxel-based analysis suggests a functional correlation between these four areas, and decreased metabolism was associated with less favorable outcomes. Higher levels of activation of the cortico-cortical connections appear to be related to better neurological condition. Differences in the thalamo-cortical correlations between patients and controls may be related to traumatic dysfunction due to focal or diffuse lesions.

Voxel-based statistical analysis of thalamic glucose metabolism in traumatic brain injury: relationship with consciousness and cognition.

OBJECTIVE: To study the relationship between thalamic glucose metabolism and neurological outcome after severe traumatic brain injury (TBI). METHODS: Forty-nine patients with severe and closed TBI and 10 healthy control subjects with (18)F-FDG PET were studied. Patients were divided into three groups: MCS&VS group (n = 17), patients in a vegetative or a minimally conscious state; In-PTA group (n = 12), patients in a state of post-traumatic amnesia (PTA); and Out-PTA group (n = 20), patients who had emerged from PTA. SPM5 software implemented in MATLAB 7 was used to determine the quantitative differences between patients and controls. FDG-PET images were spatially normalized and an automated thalamic ROI mask was generated. Group differences were analysed with two sample voxel-wise t-tests. RESULTS: Thalamic hypometabolism was the most prominent in patients with low consciousness (MCS&VS group) and the thalamic hypometabolism in the In-PTA group was more prominent than that in the Out-PTA group. Healthy control subjects showed the greatest thalamic metabolism. These differences in metabolism were more pronounced in the internal regions of the thalamus. CONCLUSIONS: The results confirm the vulnerability of the thalamus to suffer the effect of the dynamic forces generated during a TBI. Patients with thalamic hypometabolism could represent a sub-set of subjects that are highly vulnerable to neurological disability after TBI.

Neuro-Behcet's disease presenting with amnesia and frontal dysfunction.

We report a 48-year-old patient with neuro-Behcet's disease who presented with the combination of severe memory impairment and frontal/executive dysfunction. The clinical feature mimicked that of diencephalic amnesic syndrome. The MRI and SPECT findings supported the notion that the thalamus and related subcortical-frontal connection was responsible for this patient's problem.

Diaschisis after thalamic stroke: a comparison of metabolic and structural changes in a patient with amnesic syndrome.

INTRODUCTION: We present a patient with a left anteromedial thalamic lesion with an amnesic syndrome. The patient underwent neuropsychological testing, cerebrospinal fluid (CSF) analyses, magnetic resonance imaging (MRI) [T2, flair, and diffusion tensor imaging (DTI)] and [18F]-2-fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) to assess indirect effects of thalamic lesions on cortical function. CASE REPORT: A 67-year-old right-handed woman was admitted to a university-based memory unit because of memory and concentration problems. Neuropsychological testing revealed dysfunction of episodic memory, semantic memory and working memory. General intellectual function and attention capacity were preserved. MRI revealed an anteromedial thalamic lesion in the left hemisphere. FDG-PET showed decreased uptake in the frontal, parietal and temporal lobes of the left hemisphere. Regions of interest (ROI) in white matter were selected and left and right hemispheres were compared. Fractional anisotropy (FA) in ROI representing thalamo-cortical connections were decreased in the left hemisphere when compared with the right. CONCLUSION: The results show the importance of a network that include the anterior and dorsomedian nuclei, which influence the activity in areas of the cortex responsible for memory processes. The imaging findings suggest that areas of cortical diaschisis after thalamic infarction correspond to areas affected by thalamo-cortical fibre loss as measured with FA.

Positron emission tomographic study of post-ischaemic-hypoxic amnesia.

BACKGROUND: Despite extensive research, it still remains controversial as to what the precise location of the critical lesions underlying amnesia actually is. The amnesic syndrome is believed to be heterogeneous and due to several distinct functional deficits. PATIENTS AND METHODS: Two patients, a 45-year-old woman and a 56-year-old man, with sudden cardiopulmonary arrest and successful resuscitation, were left with a clear amnesic syndrome as main neurological sequela. During their revalidation period, they underwent a positron emission tomographic (PET) examination, utilizing the (13)NH(3) bolus technique at rest and after intravenous acetazolamide administration. RESULTS: Both PET studies showed more or less similar features with a decrease in regional cerebral blood flow (rCBF) in the frontal, temporal and parietal lobes. In addition, the rCBF was increased in both thalami of the 45-year-old woman and in the striata of the 56-year-old man. Acetazolamide vasoreactivity was most lost in the frontal lobes. CONCLUSIONS: In the present PET study, we demonstrated that destruction of the inhibitory pathways to the thalamus and basal ganglia by ischaemic-hypoxic frontal lesions could be one of the mechanisms leading to amnesia.

Voxel-based mapping of brain hypometabolism in permanent amnesia with PET.

In this study, we used voxel-based mapping methods to compare the resting cerebral metabolic rate of glucose (CMRglc) measured with PET in five patients with permanent amnesia (three with chronic Wernicke-Korsakoff and two with postanoxia syndrome) to that of nine healthy age-matched subjects. We assessed (i) a group pattern of relative hypometabolism; and (ii) the consistency of this group pattern, if any, in individual subjects, according to etiology. The results from the group analysis documented that permanent amnesia is associated with hypometabolism in the thalamus, posterior cingulate cortex, and mesial prefrontal cortex (near the anterior cingulate gyrus), bilaterally, as well as in the left supramarginal and middle temporal gyri. The individual analysis showed that this group pattern was found in essentially each patient, regardless of the cause of amnesia. Thus, permanent amnesia is subtended by dysfunction in structures belonging to Papez/limbic circuits as well as in left-hemisphere areas typically concerned with verbal functions, probably through a mechanism of thalamo-cortical disconnection and possibly involved in retrograde amnesia. The use of a voxel-based method allowed us to map a common network of synaptic dysfunction in a neuropsychological syndrome regardless of etiology. Our results indicate that this should be a powerful method in functional neuropsychology.

Loss of psychic self-activation after paramedian bithalamic infarction.

BACKGROUND AND PURPOSE: Loss of psychic self-activation has been described after bilateral lesions to the globus pallidus, striatum, and white matter of the frontal lobes, but it is a very rare sign of bithalamic lesions. The exact functional-anatomic mechanism underlying loss of psychic self-activation following bithalamic lesions remains to be elucidated. CASE DESCRIPTION: We present clinical, neuropsychological, structural, and functional neuroimaging data of an 18-month follow-up period of a man with prominent loss of psychic self-activation after coronary arteriography. Except for memory decline, accompanying symptoms remained restricted to the acute phase. The neurobehavioral syndrome consisted mainly of apathy, indifference, poor motivation, and flattened affect, and this remained unchanged during the entire follow-up period. MRI showed a bithalamic infarction involving the nucleus medialis thalami bilaterally. Single-photon emission CT revealed a severe relative hypoperfusion of both thalami, a relative hypoperfusion of both nuclei caudati, and a relative hypoperfusion mesiofrontally. CONCLUSIONS: Single-photon emission CT data support the hypothesis that the neurobehavioral manifestations after bithalamic paramedian infarction are caused by disruption of the striatal-ventral pallidal-thalamic-frontomesial limbic loop. Probably, bilateral disruption at different levels of the striatal-ventral pallidal-thalamic-frontomesial loop may lead to a similar clinical picture consisting of loss of psychic self-activation.

FDG-PET analysis and findings in amnesia resulting from hypoxia.

The assumptions underlying neuroimaging, and problems in its analysis and interpretation, are commonly underestimated in neuropsychology. The ways in which fluoro-deoxy-glucose (FDG) positron emission tomography (PET) data can be analysed are discussed. PET findings from four patients who had suffered severe amnesia, following episodes of acute hypoxia, are presented. These patients had shown evidence of medial temporal (hippocampal and parahippocampal) atrophy on MRI brain scans. The PET data were analysed in several different ways. The converging findings were that the patients showed bilateral thalamic hypometabolism, and there was also evidence of retrosplenial hypometabolism bilaterally. Cognitively, these patients performed most like other patients with medial temporal lesions, but the results indicate that structural lesions can have distal metabolic effects on structures elsewhere. These findings are interpreted in the light of neuroanatomical observations concerning parallel projections between medial temporal lobe structures and the thalamus, some of which pass via the retrosplenium.

Pure amnesia after unilateral left polar thalamic infarct: topographic and sequential neuropsychological and metabolic (PET) correlations.

A 54-year-old patient who had an isolated small polar thalamic infarct and acute global amnesia with slight frontal type dysfunction but without other neurological dysfunction was studied. Memory improved partially within 8 months. At all stages the impairment was more severe for verbal than non-verbal memory. Autobiographic recollections and newly acquired information tended to be disorganised with respect to temporal order. Procedural memory was unaffected. Both emotional involvement and pleasure in reading were lost. On MRI, the infarct was limited to the left anterior thalamic nuclei and the adjacent mamillothalamic tract. The regional cerebral metabolic rate of glucose (measured with PET) was decreased on the left in the thalamus, amygdala, and posterior cingulate cortex 2 weeks after the infarct, and in the thalamus and posterior cingulate cortex 9 months later. These findings stress the specific role of the left anterior thalamic region in memory and confirm that longlasting amnesia from a thalamic lesion can occur without significant structural damage to the dorsomedial nucleus. Furthermore, they suggest that the anterior thalamic nuclei and possibly their connections with the posterior cingulate cortex play a role in emotional involvement linked to ipsilateral hemispheric functions.

Metabolic impairment in human amnesia: a PET study of memory networks.

Human amnesia is a clinical syndrome exhibiting the failure to recall past events and to learn new information. Its "pure" form, characterized by a selective impairment of long-term memory without any disorder of general intelligence or other cognitive functions, has been associated with lesions localized within Papez's circuit and some connected areas. Thus, amnesia could be due to a functional disconnection between components of this or other neural structures involved in long-term learning and retention. To test this hypothesis, we measured regional cerebral metabolism with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in 11 patients with "pure" amnesia. A significant bilateral reduction in metabolism in a number of interconnected cerebral regions (hippocampal formation, thalamus, cingulate gyrus, and frontal basal cortex) was found in the amnesic patients in comparison with normal controls. The metabolic impairment did not correspond to alterations in structural anatomy as assessed by magnetic resonance imaging (MRI). These results are the first in vivo evidence for the role of a functional network as a basis of human memory.

Thalamic ischemia in transient global amnesia: a SPECT study.

We performed 99mTc-HMPAO SPECT in a patient during transient global amnesia and twice thereafter. SPECT during the attack showed a significant diminution of regional blood flow in the left thalamus and a less marked diminution in the right thalamus. Quantitative evaluation of global 99mTc-HMPAO uptake indicated a diffuse depression of cerebral blood flow. At follow-up to 40 days after the attack, global uptake and thalamic flow indices normalized, but there was a persistent reduction of left frontal flow values.

Cerebral blood flow and metabolism in an amnestic patient with left thalamic infarction--a positron emission tomographic study.

A 30-year-old man with left thalamic infarction developed severe amnesia. The positron emission tomography showed a decrease in cerebral blood flow and oxygen metabolism in the left thalamus and the ipsilateral frontal cortex (-20% to -12% of asymmetry index) both at day 11 and at 5 months after onset, although amnestic symptoms certainly improved during that period. The selective hypometabolism of the cerebral cortex suggested the remote effects of neuronal fiber disconnection between the left thalamus and the ipsilateral frontal cortex, which did not parallel the clinical course.

Pure amnesia in a case of right thalamic lesion.

A 50 year old righthanded woman had a sudden attack of disorientation in time and loss of memory. On admission she was found to have a left pyramidal hemisyndrome and a small hypodensity in the right thalamus on CT scanning. Neuropsychological examination revealed a normal short term verbal memory and some impairment of episodic long term memory, which improved after 3 months and normalized completely within a year.

The paramedian diencephalic syndrome: a dynamic phenomenon.

The paramedian diencephalic syndrome is characterized by a clinical triad: hypersomnolent apathy, amnesic syndrome, and impaired vertical gaze. We studied 4 cases with computed tomography evidence of bilateral diencephalic infarctions. Each case began abruptly with hypersomnolent apathy followed by fluctuations from appropriate affect, full orientation, and alertness to labile mood, confabulation, and apathy. Speech varied from hypophonia to normal; handwriting varied from legible script to gross scrawl. Psychological testing revealed poor learning and recall, with low performance scores. In 3 patients the predominant abnormality was in downward gaze.

Dorsal thalamic lesion in a noted case of human memory dysfunction.

The extensively studied patient N.A. has had a severe verbal memory deficit since 1960, when he sustained a stab wound to the brain with a miniature fencing foil. His amnesia occurs in the absence of any other known cognitive defect. Recent CT scans have localized a lesion in the left dorsal thalamus of this patient in a position corresponding to the dorsomedial nucleus; there is no radiographic evidence of other damage in the diencephalon or cerebral cortex. The dorsomedial thalamus may be critical in the neuropathology of diencephalic amnesia and, in humans, may be required for normal memory functions.