Pathological Slow-Wave Activity and Impaired Working Memory Binding in Post-Traumatic Amnesia.

Associative binding is key to normal memory function and is transiently disrupted during periods of post-traumatic amnesia (PTA) following traumatic brain injury (TBI). Electrophysiological abnormalities, including low-frequency activity, are common following TBI. Here, we investigate associative memory binding during PTA and test the hypothesis that misbinding is caused by pathological slowing of brain activity disrupting cortical communication. Thirty acute moderate to severe TBI patients (25 males; 5 females) and 26 healthy controls (20 males; 6 females) were tested with a precision working memory paradigm requiring the association of object and location information. Electrophysiological effects of TBI were assessed using resting-state EEG in a subsample of 17 patients and 21 controls. PTA patients showed abnormalities in working memory function and made significantly more misbinding errors than patients who were not in PTA and controls. The distribution of localization responses was abnormally biased by the locations of nontarget items for patients in PTA, suggesting a specific impairment of object and location binding. Slow-wave activity was increased following TBI. Increases in the δ-α ratio indicative of an increase in low-frequency power specifically correlated with binding impairment in working memory. Connectivity changes in TBI did not correlate with binding impairment. Working memory and electrophysiological abnormalities normalized at 6 month follow-up. These results show that patients in PTA show high rates of misbinding that are associated with a pathological shift toward lower-frequency oscillations.SIGNIFICANCE STATEMENT How do we remember what was where? The mechanism by which information (e.g., object and location) is integrated in working memory is a central question for cognitive neuroscience. Following significant head injury, many patients will experience a period of post-traumatic amnesia (PTA) during which this associative binding is disrupted. This may be because of electrophysiological changes in the brain. Using a precision working memory test and resting-state EEG, we show that PTA patients demonstrate impaired binding ability, and this is associated with a shift toward slower-frequency activity on EEG. Abnormal EEG connectivity was observed but was not specific to PTA or binding ability. These findings contribute to both our mechanistic understanding of working memory binding and PTA pathophysiology.

Exploring the use of dopaminergic medication to treat hemispatial inattention during in-patient post-stroke neurorehabilitation.

Hemispatial inattention (HSI), a lateralised impairment of spatial processing, is a common consequence of stroke. It is a poor prognostic indicator for functional recovery and interferes with the progress during in-patient neurorehabilitation. Dopaminergic medication has shown promise in improving HSI in the chronic post-stroke period but is untested in more acute settings, e.g. during in-patient neurorehabilitation. We audited the use of dopaminergic medication in ten sequential patients with post-stroke HSI, on an open-label exploratory basis. Patients' response to medication was assessed individually, using a three-week Off-On-Off protocol. We employed a mixture of bedside and functional measures, and made a multidisciplinary judgement of efficacy in individual patients. In six out of 10 patients, there was a convincing improvement of HSI while on medication, which reversed when it was paused. There was a mean 57% relative increase in target detection in the star cancellation test on the most affected side (on vs. off medication). In the six responders, medication was therefore continued throughout their admission without adverse effects. The star cancellation test was sensitive to HSI in most patients but in two cases failed to detect changes that were picked up by a functional assessment (Kessler Functional Neglect Assessment Protocol). We found this multidisciplinary approach to be feasible in an in-patient neurorehabilitation setting. We suggest further research to explore the efficacy of dopaminergic medication in improving neurorehabilitation outcomes for patients with post-stroke HSI. We suggest that more detailed N-of-1 assessments of treatment response, with internal blinding, may be a productive approach.

Abnormal dorsal attention network activation in memory impairment after traumatic brain injury.

Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injury patients we examined whether: (i) impairments in memory encoding are associated with abnormal brain activation in these networks; (ii) whether changes in this brain activity predict subsequent memory retrieval; and (iii) whether abnormal white matter integrity underpinning functional networks is associated with impaired subsequent memory. Thirty-five patients with moderate-severe traumatic brain injury aged 23-65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy control subjects underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network. Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal change between patients with and without memory impairment, suggesting that memory encoding mechanisms could be fundamentally altered in this population. We demonstrate a clear relationship between functional networks activated during encoding and underlying abnormalities within the structural connectome in patients with memory impairment. We suggest that encoding failures in this group are likely due to failed control of goal-directed attentional resources.

Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models.

Cyclin-dependent-like kinase 5 (CDKL5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)-derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of CDKL5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent signaling, which are disrupted in both CDKL5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury.

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF ß amyloid 1-42 (Aß42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.

Cognitive impairment and health-related quality of life following traumatic brain injury.

BACKGROUND: Cognitive impairment is a common and disabling consequence of traumatic brain injury (TBI) but its impact on health-related quality of life is not well understood. OBJECTIVE: To investigate the relationship between cognitive impairment and health-related quality of life (HRQoL) after TBI. METHODS: Retrospective, cross-sectional study of a specialist TBI outpatient clinic patient sample. OUTCOME MEASURES: Addenbrooke's Cognitive Examination Tool - Revised (ACE-R), and SF-36 quality of life, Beck Depression Inventory II (BDI-II), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires. RESULTS: 240 adults were assessed: n = 172 (71.7%) moderate-severe, 41 (23.8%) mild, 27 (11.3%) symptomatic TBI, 174 (72.5%) male, median age (range): 44 (22-91) years. TBI patients reported poorer scores on all domains of SF-36 compared to age-matched UK normative data. Cognitively impaired patients reported poorer HRQoL on the physical, social role and emotional role functioning, and mental health domains. Cognitive impairment predicted poorer HRQoL on the social and emotional role functioning domains, independently of depressive symptoms, sleep disturbance, daytime sleepiness and TBI severity. Mediation analysis revealed that the effect of depressive symptoms on the emotional role functioning domain of HRQoL was partially mediated by cognitive dysfunction. CONCLUSION: Cognitive impairment is associated with worse health-related quality of life after TBI and partially mediates the effect of depressive symptoms on emotional role functioning.

Randomised, double-blind, placebo-controlled crossover study of single-dose guanfacine in unilateral neglect following stroke.

OBJECTIVE: Unilateral neglect is a poststroke disorder that impacts negatively on functional outcome and lacks established, effective treatment. This multicomponent syndrome is characterised by a directional bias of attention away from contralesional space, together with impairments in several cognitive domains, including sustained attention and spatial working memory. This study aimed to test the effects of guanfacine, a noradrenergic alpha-2A agonist, on ameliorating aspects of neglect. METHODS: Thirteen right hemisphere stroke patients with leftward neglect were included in a randomised, double-blind, placebo-controlled proof-of-concept crossover study that examined the effects of a single dose of guanfacine. Patients were tested on a computerised, time-limited cancellation paradigm, as well as tasks that independently assessed sustained attention and spatial working memory. RESULTS: On guanfacine, there was a statistically significant improvement in the total number of targets found on the cancellation task when compared with placebo (mean improvement of 5, out of a possible 64). However, there was no evidence of a change in neglect patients' directional attention bias. Furthermore, Bayesian statistical analysis revealed reliable evidence against any effects of guanfacine on search organisation and performance on our sustained attention and spatial working memory tasks. CONCLUSIONS: Guanfacine improves search in neglect by boosting the number of targets found but had no effects on directional bias or search organisation, nor did it improve sustained attention or working memory on independent tasks. Further work is necessary to determine whether longer term treatment with guanfacine may be effective for some neglect patients and whether it affects functional outcome measures. TRIAL REGISTRATION NUMBER: NCT00955253.

Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. METHODS: Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). RESULTS: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. INTERPRETATION: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43.

CD8+ encephalitis: a severe but treatable HIV-related acute encephalopathy.

Rapidly progressive encephalopathy in an HIV-positive patient presents a major diagnostic and management challenge. CD8+ encephalitis is a severe but treatable form of HIV-related acute encephalopathy, characterised by diffuse perivascular and intraparenchymal CD8+ lymphocytic infiltration. It can occur in patients who are apparently stable on antiretroviral treatment and probably results from viral escape into the central nervous system. Treatment, including high-dose corticosteroids, can give an excellent neurological outcome, even in people with severe encephalopathy and a very poor initial neurological status. We report a woman with CD8+ encephalitis, with a normal CD4 count and undetectable serum viral load, who made a good recovery despite the severity of her presentation.

NMDA-receptor associated encephalitis in a woman with mature cystic ovarian teratoma.

Introduction - N-methyl-D-aspartate receptor (NMDA-R) antibody-associated encephalitis has been reported in the international neurological literature to be associated with mature or immature ovarian teratomas (OTs). However, few cases of encephalitis were diagnosed in Hungary. In 2011 Hollody et al. described the first case of anti-NMDA receptor associated encephalitis in Hungary. Objective - Our aim was to present a case of NMDA-R antibody-mediated encephalitis in a woman with OT thereby providing information facilitating diagnosis of OT in women, who present with symptoms of encephalitis. Case - We report the case of a 25 year-old women, who developed NMDA-R -antibody associated autoimmune encephalitis and who displayed confusion, disorientation, a behavioural disturbance with agitation and features of paranoia and at least one reported generalized tonic clonic seizure and orofacial dyskinesia. Magnetic resonance imaging revealed a functional ovarian cyst measuring 3.3 cm, which was removed surgically and demonstrated histologically to be a mature cystic OT. The serum was positive for antibodies to NMDA receptors. Following intravenous immunoglobulin treatment, oophorectomy and a 5-day course of plasma exchange, followed by corticosteroid and azathioprine immunosuppressive therapy, the patient displayed a significant clinical improvement. Conclusion - Cystic teratomas are common benign ovarian lesions in women of reproductive age. Although the association of OTs and NMDA-R antibody-associated encephalitis has been described in the international neurological literature, this relationship needs to be considered from on the interdisciplinary aspect by the health care providers.

Eye-Search: A web-based therapy that improves visual search in hemianopia.

Persisting hemianopia frequently complicates lesions of the posterior cerebral hemispheres, leaving patients impaired on a range of key activities of daily living. Practice-based therapies designed to induce compensatory eye movements can improve hemianopic patients' visual function, but are not readily available. We used a web-based therapy (Eye-Search) that retrains visual search saccades into patients' blind hemifield. A group of 78 suitable hemianopic patients took part. After therapy (800 trials over 11 days), search times into their impaired hemifield improved by an average of 24%. Patients also reported improvements in a subset of visually guided everyday activities, suggesting that Eye-Search therapy affects real-world outcomes.

Working memory recall precision is a more sensitive index than span.

Delayed adjustment tasks have recently been developed to examine working memory (WM) precision, that is, the resolution with which items maintained in memory are recalled. However, despite their emerging use in experimental studies of healthy people, evaluation of patient populations is sparse. We first investigated the validity of adjustment tasks, comparing precision with classical span measures of memory across the lifespan in 114 people. Second, we asked whether precision measures can potentially provide a more sensitive measure of WM than traditional span measures. Specifically, we tested this hypothesis examining WM in a group with early, untreated Parkinson's disease (PD) and its modulation by subsequent treatment on dopaminergic medication. Span measures correlated with precision across the lifespan: in children, young, and elderly participants. However, they failed to detect changes in WM in PD patients, either pre- or post-treatment initiation. By contrast, recall precision was sensitive enough to pick up such changes. PD patients pre-medication were significantly impaired compared to controls, but improved significantly after 3 months of being established on dopaminergic medication. These findings suggest that precision methods might provide a sensitive means to investigate WM and its modulation by interventions in clinical populations.

Binding deficits in memory following medial temporal lobe damage in patients with voltage-gated potassium channel complex antibody-associated limbic encephalitis.

Some prominent studies have claimed that the medial temporal lobe is not involved in retention of information over brief intervals of just a few seconds. However, in the last decade several investigations have reported that patients with medial temporal lobe damage exhibit an abnormally large number of errors when required to remember visual information over brief intervals. But the nature of the deficit and the type of error associated with medial temporal lobe lesions remains to be fully established. Voltage-gated potassium channel complex antibody-associated limbic encephalitis has recently been recognized as a form of treatable autoimmune encephalitis, frequently associated with imaging changes in the medial temporal lobe. Here, we tested a group of these patients using two newly developed visual short-term memory tasks with a sensitive, continuous measure of report. These tests enabled us to study the nature of reporting errors, rather than only their frequency. On both paradigms, voltage-gated potassium channel complex antibody patients exhibited larger errors specifically when several items had to be remembered, but not for a single item. Crucially, their errors were strongly associated with an increased tendency to report the property of the wrong item stored in memory, rather than simple degradation of memory precision. Thus, memory for isolated aspects of items was normal, but patients were impaired at binding together the different properties belonging to an item, e.g. spatial location and object identity, or colour and orientation. This occurred regardless of whether objects were shown simultaneously or sequentially. Binding errors support the view that the medial temporal lobe is involved in linking together different types of information, potentially represented in different parts of the brain, regardless of memory duration. Our novel behavioural measures also have the potential to assist in monitoring response to treatment in patients with memory disorders, such as those with voltage-gated potassium channel complex antibody limbic encephalitis.

The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke.

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7-11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke.

Axonal integrity predicts cortical reorganisation following cervical injury.

BACKGROUND: Traumatic spinal cord injury (SCI) leads to disruption of axonal architecture and macroscopic tissue loss with impaired information flow between the brain and spinal cord-the presumed basis of ensuing clinical impairment. OBJECTIVE: The authors used a clinically viable, multimodal MRI protocol to quantify the axonal integrity of the cranial corticospinal tract (CST) and to establish how microstructural white matter changes in the CST are related to cross-sectional spinal cord area and cortical reorganisation of the sensorimotor system in subjects with traumatic SCI. METHODS: Nine volunteers with cervical injuries resulting in bilateral motor impairment and 14 control subjects were studied. The authors used diffusion tensor imaging to assess white matter integrity in the CST, T1-weighted imaging to measure cross-sectional spinal cord area and functional MRI to compare motor task-related brain activations. The relationships among microstructural, macrostructural and functional measures were assessed using regression analyses. Results Diffusion tensor imaging revealed significant differences in the CST of SCI subjects-compared with controls-in the pyramids, the internal capsule, the cerebral peduncle and the hand area. The microstructural white matter changes observed in the left pyramid predicted increased task-related responses in the left M1 leg area, while changes in the cerebral peduncle were predicted by reduced cord area. CONCLUSION: The observed microstructural changes suggest trauma-related axonal degeneration and demyelination, which are related to cortical motor reorganisation and macrostructure. The extent of these changes may reflect the plasticity of motor pathways associated with cortical reorganisation. This clinically viable multimodal imaging approach is therefore appropriate for monitoring degeneration of central pathways and the evaluation of treatments targeting axonal repair in SCI.

Precision of working memory for visual motion sequences and transparent motion surfaces.

Recent studies investigating working memory for location, color, and orientation support a dynamic resource model. We examined whether this might also apply to motion, using random dot kinematograms (RDKs) presented sequentially or simultaneously. Mean precision for motion direction declined as sequence length increased, with precision being lower for earlier RDKs. Two alternative models of working memory were compared specifically to distinguish between the contributions of different sources of error that corrupt memory (W. Zhang & S. J. Luck, 2008 vs. P. M. Bays, R. F. G. Catalao, & M. Husain, 2009). The latter provided a significantly better fit for the data, revealing that decrease in memory precision for earlier items is explained by an increase in interference from other items in a sequence rather than random guessing or a temporal decay of information. Misbinding feature attributes is an important source of error in working memory. Precision of memory for motion direction decreased when two RDKs were presented simultaneously as transparent surfaces, compared to sequential RDKs. However, precision was enhanced when one motion surface was prioritized, demonstrating that selective attention can improve recall precision. These results are consistent with a resource model that can be used as a general conceptual framework for understanding working memory across a range of visual features.

Temporal dynamics of encoding, storage, and reallocation of visual working memory.

The process of encoding a visual scene into working memory has previously been studied using binary measures of recall. Here, we examine the temporal evolution of memory resolution, based on observers' ability to reproduce the orientations of objects presented in brief, masked displays. Recall precision was accurately described by the interaction of two independent constraints: an encoding limit that determines the maximum rate at which information can be transferred into memory and a separate storage limit that determines the maximum fidelity with which information can be maintained. Recall variability decreased incrementally with time, consistent with a parallel encoding process in which visual information from multiple objects accumulates simultaneously in working memory. No evidence was observed for a limit on the number of items stored. Cuing one display item with a brief flash led to rapid development of a recall advantage for that item. This advantage was short-lived if the cue was simply a salient visual event but was maintained if it indicated an object of particular relevance to the task. These cuing effects were observed even for items that had already been encoded into memory, indicating that limited memory resources can be rapidly reallocated to prioritize salient or goal-relevant information.