Clive R. Rosenthal

Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype.

Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346-4515 pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11-200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immunotherapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross-sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n = 13) (P < 0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenotype. Immunotherapy is associated with excellent control of the frequently anti-epileptic drug refractory seizures, hastens time to recovery, and may prevent the subsequent development of cognitive impairment observed in this study.

Theta burst stimulation reduces disability during the activities of daily living in spatial neglect

Left-sided spatial neglect is a common neurological syndrome following right-hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double-blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham stimulation or in the control group without stimulation. These results provide Class I evidence that continuous theta burst stimulation is a viable add-on therapy in neglect rehabilitation that facilitates recovery of normal everyday behaviour.

Response-Dependent Contributions of Human Primary Motor Cortex and Angular Gyrus to Manual and Perceptual Sequence Learning

Motor sequence learning on the serial reaction time task involves the integration of response-, stimulus-, and effector-based information. Human primary motor cortex (M1) and the inferior parietal lobule (IPL) have been identified with supporting the learning of effector-dependent and -independent information, respectively. Current neurocognitive data are, however, exclusively based on learning complex sequence information via perceptual-motor responses. Here, we investigated the effects of continuous theta-burst transcranial magnetic stimulation (cTBS)-induced disruption of M1 and the angular gyrus (AG) of the IPL on learning a probabilistic sequence via sequential perceptual-motor responses (experiment 1) or covert orienting of visuospatial attention (experiment 2). Functional effects on manual sequence learning were evident during 75% of training trials in the cTBS M1 condition, whereas cTBS over the AG resulted in interference confined to a midpoint during the training phase. Posttraining direct (declarative) tests of sequence knowledge revealed that cTBS over M1 modulated the availability of newly acquired sequence knowledge, whereby sequence knowledge was implicit in the cTBS M1 condition but was available to conscious awareness in the cTBS AG and control conditions. In contrast, perceptual sequence learning was abolished in the perceptual cTBS AG condition, whereas learning was intact and available to conscious awareness in the cTBS M1 and control conditions. These results show that the right AG had a critical role in perceptual sequence learning, whereas M1 had a causal role in developing experience-dependent functional attributes relevant to conscious knowledge on manual but not perceptual sequence learning.

Reflexive, Symbolic, and Affective Contributions to Eye Movements during Task Switching: Response Selection

Active vision is a dynamic process involving the flexible coordination of different gaze strategies to achieve behavioral goals. Although many complex behaviors rely on an ability to efficiently switch between gaze-control strategies, few studies to date have examined mechanisms of task level oculomotor control in detail. Here, we report five experiments in which subjects alternated between conflicting stimulus-saccade mappings within a block of trials. The first experiment showed that there is no performance cost associated with switching between pro and anti saccades. However, follow-up experiments demonstrate that whenever subjects alternate between arbitrary stimulus-saccade mappings, latency costs are apparent on the first trial after a task change. More detailed analysis of switch costs showed that latencies were particularly elevated for saccades directed toward the same location that had been the target for a saccade on the preceeding trial. This saccade inhibition of return effect was most marked when unexpected error feedbacks cued task switches, suggesting that saccade selection processes are modulated by reward. We conclude that there are two systems for saccade control that differ in their characteristics following a task switch. The reflexive control system can be enabled/disabled in advance of saccade execution without incurring any performance cost. Switch costs are only observed when two or more arbitrary stimulus-saccade mappings have to be coordinated by a symbolic control system.

Persistent anterograde amnesia following limbic encephalitis associated with antibodies to the voltage-gated potassium channel complex

Objective Limbic encephalitis (LE) associated with antibodies to the voltage-gated potassium channel complex (VGKC) is a potentially reversible cause of cognitive impairment. Despite the prominence of cognitive dysfunction in this syndrome, little is known about patients’ neuropsychological profile at presentation or their long-term cognitive outcome. Methods We used a comprehensive neuropsychological test battery to evaluate cognitive function longitudinally in 19 patients with VGKC-LE. Results Before immunotherapy, the group had significant impairment of memory, processing speed and executive function, whereas language and perceptual organisation were intact. At follow-up, cognitive impairment was restricted to the memory domain, with processing speed and executive function having returned to the normal range. Residual memory function was predicted by the antibody titre at presentation. Conclusions The results show that, despite broad cognitive dysfunction in the acute phase, patients with VGKC-LE often make a substantial recovery with immunotherapy but may be left with permanent anterograde amnesia.

Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis.

Autoantibodies linked with voltage-gated potassium channel (VGKC)-complex antibody-mediated limbic encephalitis (LE) bind to hippocampal subfields. Miller et al. report that chronic LGI1 antibody VGKC-complex LE is associated with focal CA3 atrophy on 7.0-Tesla neuroimaging and autobiographical episodic amnesia. The results point to antibody-mediated pathogenicity and CA3-mediated impairment of episodic memory.

Temporal dynamics of parietal cortex involvement in visual search

The functional-neuroanatomic relationship that describes the involvement of the parietal cortex in visual search was investigated using repetitive transcranial magnetic stimulation (rTMS; 10 Hz, 500 ms in duration). Twelve adult participants performed feature-based visual search for a unique letter-without eye movements-under conditions that involved manipulations of search efficiency (efficient versus inefficient) and target-selection demands (set-size: 4 versus 10). rTMS was applied over the right posterior parietal cortex at the onset of the search array for all factorial conditions (0-500 ms); stimulation was additionally administered at 500 ms post-array onset (500-1000 ms) during inefficient search (set-size 10). Stimulation over the primary sensorimotor cortex served as a within-subjects control condition, and eye movements were monitored continuously. Significant increases in reaction time were restricted to parietal stimulation during inefficient search (set-size 10), with interference observed when rTMS was administered at the onset of the search array and at 500 ms post-array onset. The early effect was confined to target-present trials and the late effect was confined to target-absent trials, which may indicate temporally dissociable parietal involvement in target detection and response-based selection and/or search termination, respectively. Error rates did not vary significantly as a function of any of the independent variables. Taken together, these results are consistent with evidence from functional magnetic resonance studies indicating that inefficient feature-based visual search requires an intact parietal cortex, and also indicate that the parietal cortex is involved in inefficient search later than has been previously reported.

Learning and Recognition of a Non-conscious Sequence of Events in Human Primary Visual Cortex.

Summary Human primary visual cortex (V1) has long been associated with learning simple low-level visual discriminations [1] and is classically considered outside of neural systems that support high-level cognitive behavior in contexts that differ from the original conditions of learning, such as recognition memory [2, 3]. Here, we used a novel fMRI-based dichoptic masking protocol—designed to induce activity in V1, without modulation from visual awareness—to test whether human V1 is implicated in human observers rapidly learning and then later (15–20 min) recognizing a non-conscious and complex (second-order) visuospatial sequence. Learning was associated with a change in V1 activity, as part of a temporo-occipital and basal ganglia network, which is at variance with the cortico-cerebellar network identified in prior studies of “implicit” sequence learning that involved motor responses and visible stimuli (e.g., [4]). Recognition memory was associated with V1 activity, as part of a temporo-occipital network involving the hippocampus, under conditions that were not imputable to mechanisms associated with conscious retrieval. Notably, the V1 responses during learning and recognition separately predicted non-conscious recognition memory, and functional coupling between V1 and the hippocampus was enhanced for old retrieval cues. The results provide a basis for novel hypotheses about the signals that can drive recognition memory, because these data (1) identify human V1 with a memory network that can code complex associative serial visuospatial information and support later non-conscious recognition memory-guided behavior (cf. [5]) and (2) align with mouse models of experience-dependent V1 plasticity in learning and memory [6].

Recognizing the unconscious

Summary Recognition memory enables us to discriminate whether an event has occurred in the past, and is widely interpreted to reflect the conscious retrieval of episodic traces or familiarity [1,2]. Non-conscious mnemonic influences, such as repetition priming, are thought to have a negligible effect on standard tests of recognition memory [3]. A major difficulty with this conclusion is that it is exclusively based on the results from experimental protocols that use stimulus materials available to conscious perception. In eight experiments (N = 144), we tested the necessity of mechanisms related to conscious perception for accurate recognition memory by manipulating observers’ awareness of either the encoded event and/or the retrieval cues. Remarkably, observers made accurate objective and subjective recognition memory-guided judgments without visual awareness of the encoded events, retrieval cues or, most strikingly, both. These results demonstrate that non-conscious processes can drive accurate recognition memory, and are a significant challenge to neurobiological accounts centered on the conscious retrieval of episodic traces or familiarity.

Visuospatial Sequence Learning without Seeing

Background The ability to detect and integrate associations between unrelated items that are close in space and time is a key feature of human learning and memory. Learning sequential associations between non-adjacent visual stimuli (higher-order visuospatial dependencies) can occur either with or without awareness (explicit vs. implicit learning) of the products of learning. Existing behavioural and neurocognitive studies of explicit and implicit sequence learning, however, are based on conscious access to the sequence of target locations and, typically, on conditions where the locations for orienting, or motor, responses coincide with the locations of the target sequence. Methodology/Principal Findings Dichoptic stimuli were presented on a novel sequence learning task using a mirror stereoscope to mask the eye-of-origin of visual input from conscious awareness. We demonstrate that conscious access to the sequence of target locations and responses that coincide with structure of the target sequence are dispensable features when learning higher-order visuospatial associations. Sequence knowledge was expressed in the ability of participants to identify the trained higher-order visuospatial sequence on a recognition test, even though the trained and untrained recognition sequences were identical when viewed at a conscious binocular level, and differed only at the level of the masked sequential associations. Conclusions/Significance These results demonstrate that unconscious processing can support perceptual learning of higher-order sequential associations through interocular integration of retinotopic-based codes stemming from monocular eye-of-origin information. Furthermore, unlike other forms of perceptual associative learning, visuospatial attention did not need to be directed to the locations of the target sequence. More generally, the results pose a challenge to neural models of learning to account for a previously unknown capacity of the human visual system to support the detection, learning and recognition of higher-order sequential associations under conditions where observers are unable to see the target sequence or perform responses that coincide with structure of the target sequence.