Subcortical modulation of spatial attention including evidence that the Sprague effect extends to man

The Sprague effect is well-established-small tectal lesions restore visual orientation in the hemianopic field of animals with extensive unilateral geniculo-striate lesions. Studies of human midbrain visual functions are rare. This man with a midbrain tumour developed left-neglect through subsequent right frontal damage. Bilateral orientation returned after clear evidence of damage to the superior colliculus contralateral to the cortical lesion (showing the Sprague effect extends to man). Sustained right-neglect developed after probable additional damage to right superior colliculus. The regulation of spatial attention by tecto-pulvinar circuits is discussed, and it is argued that the reduced right tecto-pulvinar activity (consequent to the additional right collicular damage) was offset by over-compensatory increase in thalamic reticular nucleus (TRN) suppression of left pulvinar activity.     

Hallucinations in schizophrenia, sensory impairment, and brain disease: a unifying model

Based on recent insight into the thalamocortical system and its role in perception and conscious experience, a unified pathophysiological framework for hallucinations in neurological and psychiatric conditions is proposed, which integrates previously unrelated neurobiological and psychological findings. Gamma-frequency rhythms of discharge activity from thalamic and cortical neurons are facilitated by cholinergic arousal and resonate in networks of thalamocortical circuits, thereby transiently forming assemblies of coherent gamma oscillations under constraints of afferent sensory input and prefrontal attentional mechanisms. If perception is based on synchronisation of intrinsic gamma activity in the thalamocortical system, then sensory input to specific thalamic nuclei may merely play a constraining role. Hallucinations can be regarded as underconstrained perceptions that arise when the impact of sensory input on activation of thalamocortical circuits and synchronisation of thalamocortical gamma activity is reduced. In conditions that are accompanied by hallucinations, factors such as cortical hyperexcitability, cortical attentional mechanisms, hyperarousal, increased noise in specific thalamic nuclei, and random sensory input to specific thalamic nuclei may, to a varying degree, contribute to underconstrained activation of thalamocortical circuits. The reticular thalamic nucleus plays an important role in suppressing random activity of relay cells in specific thalamic nuclei, and its dysfunction may be implicated in the biological vulnerability to hallucinations in schizophrenia. Combined with general activation during cholinergic arousal, this leads to excessive disinhibition in specific thalamic nuclei, which may allow cortical attentional mechanisms to recruit thalamic relay cells into resonant assemblies of gamma oscillations, regardless of their actual sensory input, thereby producing an underconstrained perceptual experience.     

Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness

A unifying theory of general anesthetic-induced unconsciousness must explain the common mechanism through which various anesthetic agents produce unconsciousness. Functional-brain-imaging data obtained from 11 volunteers during general anesthesia showed specific suppression of regional thalamic and midbrain reticular formation activity across two different commonly used volatile agents. These findings are discussed in relation to findings from sleep neurophysiology and the implications of this work for consciousness research. It is hypothesized that the essential common neurophysiologic mechanism underlying anesthetic-induced unconsciousness is, as with sleep-induced unconsciousness, a hyperpolarization block of thalamocortical neurons. A model of anesthetic-induced unconsciousness is introduced to explain how the plethora of effects anesthetics have on cellular functioning ultimately all converge on a single neuroanatomic/neurophysiologic system, thus providing for a unitary physiologic theory of narcosis related to consciousness.     

Cerebral blood flow differences between long-term meditators and non-meditators

We have studied a number of long-term meditators in previous studies. The purpose of this study was to determine if there are differences in baseline brain function of experienced meditators compared to non-meditators. All subjects were recruited as part of an ongoing study of different meditation practices. We evaluated 12 advanced meditators and 14 non-meditators with cerebral blood flow (CBF) SPECT imaging at rest. Images were analyzed with both region of interest and statistical parametric mapping. The CBF of long-term meditators was significantly higher (p < .05) compared to non-meditators in the prefrontal cortex, parietal cortex, thalamus, putamen, caudate, and midbrain. There was also a significant difference in the thalamic laterality with long-term meditators having greater asymmetry. The observed changes associated with long-term meditation appear in structures that underlie the attention network and also those that relate to emotion and autonomic function.     

Escape from deficits in sodium intake after thalamic lesions as a function of preoperative experience

Saline and water intakes in response to treatments with a natriuretic agent and a mineralocorticoid were studied in intact rats and in rats with lesions centered in the taste delay of the thalamus. Intact rats responded to the treatments by increasing both saline and water intake. Rats with thalamic lesions that had never drunk saline prior to induction of the lesions generally did not increase their saline intake in response to the treatments but showed normal increases in water intake. In contrast, rats with thalamic lesions that had drunk saline prior to induction of the lesions showed normal increases in both saline and water intake. Preoperative experience of sodium need did not protect rats against the lesion-induced deficit.     

Episodic memory, amnesia, and the hippocampal-anterior thalamic axis

By utilizing new information from both clinical and experimental (lesion, electrophysiological, and gene-activation) studies with animals, the anatomy underlying anterograde amnesia has been reformulated. The distinction between temporal lobe and diencephalic amnesia is of limited value in that a common feature of anterograde amnesia is damage to part of an "extended hippocampal system" comprising the hippocampus, the fornix, the mamillary bodies, and the anterior thalamic nuclei. This view, which can be traced back to Delay and Brion (1969), differs from other recent models in placing critical importance on the efferents from the hippocampus via the fornix to the diencephalon. These are necessary for the encoding and, hence, the effective subsequent recall of episodic memory. An additional feature of this hippocampal-anterior thalamic axis is the presence of projections back from the diencephalon to the temporal cortex and hippocampus that also support episodic memory. In contrast, this hippocampal system is not required for tests of item recognition that primarily tax familiarity judgements. Familiarity judgements reflect an independent process that depends on a distinct system involving the perirhinal cortex of the temporal lobe and the medial dorsal nucleus of the thalamus. In the large majority of amnesic cases both the hippocampal-anterior thalamic and the perirhinal-medial dorsal thalamic systems are compromised, leading to severe deficits in both recall and recognition.     

Midbrain-hypothalamic interrelationships in the control of aggressive behavior

Previous studies have suggested an involvement of the midbrain ventral tegmental area in the biting attack upon a rat elicited by electrical stimulation of the lateral hypothalamus in cats. In order assess further the relationship between these two regions, 12 cats were implanted with attack-eliciting electrodes in both the lateral hypothalamus and the midbrain ventral tegmental area. Following a lesion of the midbrain attack site, attack previously elicited from hypothalamic electrodes ipsilateral to the lesion was eliminated or significantly reduced in frequency. The attack elicited from electrodes in the hypothalamus contralateral to the lesion was unaffected. Midbrain lesions made at sites from which attack was never elicited had no effect on hypothalamically elicited attack. The midbrain lesion in some cases eliminated only certain components of the total attack pattern; for example, the approach of a cat to the rat frequently remained present while the bite was absent. Additionally, it was found that the attack elicited from rostral hypothalamic electrodes was disrupted to a greater degree by a single midbrain lesion than the attack elicited from more caudal hypothalamic electrodes. These finding are discussed in terms of the neural system mediating this form of aggressive behavior in cats.     

Subcortical mechanisms in language: lexical-semantic mechanisms and the thalamus.

Four previously published cases of dominant thalamic lesion in which the author has participated are reviewed to gain a better understanding of thalamic participation in lexical-semantic functions. Naming deficits in two cases support Nadeau and Crosson's (1997) hypothesis of a selective engagement mechanism involving the frontal lobes, inferior thalamic peduncle, nucleus reticularis, and other thalamic nuclei, possibly the centromedian nucleus. This mechanism selectively engages those cortical areas required to perform a cognitive task, while maintaining other areas in a state of relative disengagement. Deficits in selective engagement disproportionately affect lexical retrieval based on semantic input, as opposed to lexical and sublexical processes, because the former is more dependent upon this attentional system. The concept of selective engagement is also useful in understanding thalamic participation in working memory, as supported by data from one recent functional neuroimaging study. Other processes also may be compromised in more posterior thalamic lesions which damage the pulvinar but not other components of this selective engagement system. A third case with aphasia after a more superior and posterior thalamic lesion also had oral reading errors similar to those in neglect dyslexia. The pattern of deficits suggested a visual processing problem in the early stages of reading. The fourth case had a category-specific naming deficit after posterior thalamic lesion. Taken together, the latter two cases indicate that the nature of language functions in more posterior regions of the dominant thalamus depends upon the cortical connectivity of the thalamic region. Together, findings from the four cases suggest that thalamic nuclei and systems are involved in multiple processes which directly or indirectly support cortical language functions.     

The role of the human thalamus in language and memory: evidence from electrophysiological studies

The data reviewed here indicate that electrical stimulation of the dominant ventrolateral thalamus can produce deficits in language processing that are not seen after similar stimulation of the nondominant ventrolateral thalamus. The nature of the language deficit produced varies, depending upon the rostrocaudal location of the stimulation site. Stimulation of the anterior left ventrolateral thalamus in right-handed patients resulted in production of a repeated erroneous word, stimulation of the medial ventrolateral thalamus evoked perseveration, and stimulation of the posterior ventrolateral thalamus and anterior pulvinar resulted in misnaming and omissions. Additional studies have examined the effect of electrical thalamic stimulation on verbal and nonverbal short-term memory. Left (but not right) ventrolateral thalamic stimulation during verbal memory input greatly decreased subsequent recall errors, while stimulation during verbal memory retrieval increased recall errors. This finding contrasted with those obtained from studies on nonverbal memory, in which right ventrolateral stimulation during memory input decreased recall errors, while left thalamic stimulation at the same stage increased recall errors. Left pulvinar stimulation disrupted verbal memory processing, while right pulvinar stimulation disrupted nonverbal memory processing. Limited evidence suggests that the effects of thalamic electrical stimulation on verbal memory may persist for several days after the stimulation has ended. The lateralization of thalamic functions also affects the motoric aspects of speech production. Left (but not right) ventrolateral thalamic stimulation disrupted speech articulation and increased the expiratory phase of respiration. The fact that these motor effects were evoked from the same general area of the thalamus that produced the language deficits discussed above raises the possibility that the thalamus is involved in coordinating the cognitive and motoric aspects of language production. A model of thalamic function is discussed in which defined regions of the thalamus operate as a "specific alerting response," increasing the input to memory of category-specific material while simultaneously inhibiting retrieval from memory.     

Mesothalamic discharge in a chronic pain,allergy and fluid retention syndrome (case report)

A 32-year-old woman was bedridden for a year because of chronic pain and headaches. She had insomnia, depression, suicidal thoughts and a severe chemical allergy. She had been on steroid therapy for two years and became Cushingoid with striae in the arm pits, groins and abdomen. However, she had no hypertension, nor the buffalo fat and hirsutism. She was very edematous, with a weight gain from 112 to 180 lbs. The fluid retention did not conform to the syndrome of inappropriate antidiuretic hormone. Studies revealed abnormal scalp EEG discharges and high-voltage seizure discharges in the posterior thalamus. Electrothalamic stimulation suppressed the thalamic discharges and relieved the patient’s pelvic pain and headaches. After one month of several thalamic stimulations per day, she was able to get out of bed and ambulate. In addition, the patient no longer was edematous and was tolerating perfumes and floor detergents. Steroids were progressively reduced without complications of withdrawal. She went from a completely steroid dependent state to independent during the first 1-1/2 yrs of thalamic stimulation. With continued thalamic stimulation she has done well for 8-1/2 yrs, weighs 112 lbs, keeps house and drives a car. It’s speculated the illness is a chronic pain multiple system syndrome predominantly due to mesothalamic discharges and body infirmities. The mesothalamic discharge implicated neural networks, which represent biologic systems, i.e. pain, sleep, fluid retention, etc. Therapeutic stimulation attenuates the discharges and the neural networks return to their normal set points of homeostasis.     

Visual aspects of centrally elicited attack behavior in the cat: “Patterned reflexes” associated with selection of and approach to a rat

It has been previously suggested that the electrical brain stimulation which elicits quiet-biting attack in the cat actively affects the way the central nervous system processes visual and tactile information concerned with the reflexes involved in the terminal aspects of attack. In order to examine the effects of brain stimulation on a nonterminal aspect of attack – the stimulated cat's selection of and approach to a rat – cats were implanted with attack-eliciting electrodes in both the lateral hypothalamus and the midbrain ventral tegmental area. These cats were then tested in an 8-ft-long cage, one end of which was divided into three, 2-ft-long parallel compartments, whose openings faced the end of the cage from which the cat commenced its approach. An anesthetized rat was placed at the back of one compartment, a bowl of food at the back of another compartment, and the third compartment contained no object. It was found in the first experiment that the attack elicited by nearly all electrodes was selectively directed at the rat. However, the success of the cat in finding the compartment containing the rat varied dramatically for different electrodes in the same cat. Further, these differences were stable and did not change as the cat gained experience with the task. The results suggested that the stimulation of different brain sites in the same cat differentially affected the visual neural mechanisms involved in guiding a cat to a rat. Previous studies have also suggested that the effects of brain stimulation which elicits quiet-biting attack are largely lateralized to the side of the brain stimulated. In order to determine if the effects of stimulation on the neural mechanisms mediating the visually guided approach of a cat to a rat were also lateralized, attempts were made in a second experiment to disrupt the visual input to one side of the brain by unilaterally transecting the optic tract. It was found that this manipulation interfered with the visually guided selective approach to a rat, if the cat was stimulated through hypothalamic or mid-brain electrodes ipsilateral to the optic tract transection, but not if the hypothalamic or midbrain stimulation was on the contralateral (visually intact) side of the brain. However, any final interpretation of the results was confounded by the finding in all of these cats of a complex syndrome of neglect of all contralateral sensory information.     

Changes of Cingulothalamic Topographic Excitation Patterns and Avoidance Response Incubation over Time Following Initial Discriminative Conditioning in Rabbits

Neurons in particular layers of cingulate cortex and in limbic thalamic nuclei exhibit peak firing rates in response to a positive conditional stimulus (CS+) in particular stages of discriminative learning. A given area is maximally activated by the CS+ in the initial, an intermediate, or a late stage of behavioral acquisition, and activation in all of the areas diminishes as training continues after the peak of activation occurs. Thus, the topographic distribution of activation in these areas depends on the stage of behavioral acquisition. The present study determined whether the acquisition-related changes of the topographic distributions of peak firing rates in CS-elicited activity are driven exclusively by the repetition of conditioning trials (i.e., practice) or may occur as well with the passage of time, similar to putative processes of memory consolidation. Multiunit activity was recorded in cingulate cortex and in the anterior dorsal (AD), anterior ventral (AV), and medial dorsal (MD) thalamic nuclei as rabbits learned to step in response to a warning tone (CS+) to prevent a scheduled foot-shock, and to ignore a different tone (CS-) not predictive of foot-shock. The rabbits received two training sessions, S1 and S2. S2 followed S1 immediately in one group of rabbits and after 48 h in a different group. Significant neuronal discharge increments occurred from S1 to S2 in the 48-h group but not in the 0-h group, for the areas (posterior cingulate cortex, AV thalamic nucleus) that previously showed only late-stage activation. Significant discharge increments occurred from S1 to S2 in the 0-h group but not in the 48-h group in areas (anterior cingulate cortex, the AD, and MD thalamic nuclei) that previously exhibited early stage activation. These results indicate that the trial-driven topographic distribution changes also occur with the passage of time after limited initial training. It is suggested that the trial-driven and time-related changes may have a common functional relevance concerning memory consolidation.     

Pathological laughter as a symptom of midbrain infarction

Pathological laughter is an uncommon symptom usually caused by bilateral, diffuse cerebral lesions. It has rarely been reported in association with isolated cerebral lesions. Midbrain involvement causing pathological laughter is extremely unusual. We describe three patients who developed pathological laughter after midbrain and pontine-midbrain infarction. In two patients a small infarction in the left paramedian midbrain was detected, whereas the third one sustained a massive bilateral pontine infarction extending to the midbrain. Laughter heralded stroke by one day in one patient and occurred as a delayed phenomenon three months after stroke in another. Pathological laughter ceased within a few days in two patients and was still present at a two year follow-up in the patient with delayed-onset laughter. Pathological laughter can herald midbrain infarction or follow stroke either shortly after onset of symptoms or as a delayed phenomenon. Furthermore, small unilateral midbrain infarctions can cause this rare complication.     

Patterns of impaired verbal,spatial, and object working memory after thalamic lesions

Working memory processes in six individuals with isolated thalamic lesions were assessed. Participants were given a verbal, spatial, and object n-back task, each at three levels of task load (1-back, 2-back, and 3-back). Relative to a control group, the patients were impaired on the verbal and spatial n-back tasks, and possibly on the object n-back task as well. None of the patients showed impaired short-term memory as measured by digit span. Group differences on trials measuring matching, sequencing, and inhibitory abilities were consistent with other reports suggesting that thalamic lesions may impair the operation of executive processes.     

Fornix, medial prefrontal cortex, nucleus accumbens, and mediodorsal thalamic nucleus: roles in a fear-based context discrimination task

The goal of the present study was to evaluate the contributions of various brain structures anatomically and functionally linked to the hippocampus and amygdala in a fear-based context discrimination task. The brain areas of interest included the fornix, medial prefrontal cortex, mediodorsal (MD) thalamic nucleus, and nucleus accumbens. Damage to the MD thalamic nucleus and medial prefrontal cortex produced the largest impairment in context-specific fear responses. Damage to the fornix impaired some fear responses (freezing, ultrasonic vocalizations, defecation, and approach/avoidance) while leaving conditioned fear expression of heart rate and urination unaltered. Damage to the nucleus accumbens was also coupled with deficits in the discriminative expression of some (heart rate, urination, and ultrasonic vocalizations) but sparing of context-appropriate freezing, defecation, and approach/avoidance behaviors.     

The neural pathways mediating quiet-biting attack behavior from the hypothalamus in the cat: A functional autoradiographic study

Electrical stimulation of the region of the lateral hypothalamus produced a consistent form of quiet-biting attack behavior in cats. In one series of experiments, cats, implanted with electrodes from which attack had been elicited, were anesthetized and then were injected with a bolus of ¹⁴C-2-deoxyglucose at the same time as electrical stimulation was delivered through the attack electrodes. Brains prepared for X-ray autoradiography revealed that lateral hypothalamic stimulation activated the classical medial forebrain bundle pathway supplying the septal region, diagonal band, lateral preoptic area, and ventral tegmental region. Stimulation of quiet-attack sites in perifornical hypothalamus resulted in the activation of a much more extensive projection system which included the central and lateral tegmental fields of the midbrain and pons, and central gray region, as well as the structures described above. In a second series of experiments, ³H-leucine was placed into the region of the electrode tip from which attack was elicited in order to identify more precisely the pathways arising from that site. In general, tritiated amino acid radioautography replicated the ¹⁴C-2-deoxyglucose findings. In addition, the amino acid radioautographic data revealed the presence of extensive projections from perifornical hypothalamus to such pontine structures as the nucleus locus coeruleus, motor nucleus of NV , and the lateral pontine tegmental field. The functional connections between the lateral hypothalamic “attack region” and lateral preoptic zone were also confirmed by electrophysiological methods.     

Medial dorsal thalamic lesions and working memory in the rat

Pigmented rats of the DA strain with either radiofrequency or ibotenic acid lesions of the thalamic nucleus medialis dorsalis were postoperatively given nonspatial and spatial tests of working memory. In the nonspatial task, delayed nonmatching-to-sample, rats with both types of thalamic lesions showed acquisition impairments. The subgroup of rats with nucleus medialis dorsalis lesions that were able to reach the acquisition criterion did, however, perform normally when the retention interval was extended to 60 s. In the spatial task, delayed forced-alternation, rats were tested with differing retention intervals and with both spaced and massed trials. Damage to nucleus medialis dorsalis had no effect on acquisition or on spaced trials, but a slight deficit was found in the animals with radiofrequency lesions under the massed trial condition. Much clearer deficits were, however, present in those animals in which the lesion extended appreciably into the anterior thalamic nuclei. The findings indicate that while cellular damage to nucleus medialis dorsalis may disrupt learning, some impairments in tests of spatial working memory attributed to this nucleus may reflect damage to the adjacent anterior thalamic nuclei.     

Motivated behaviors elicited from hypothalamus, midbrain, and pons of the guinea pig (Cavia porcellus).

Eating, drinking, biting attack, male mating behavior, and gnawing were elicited by electrical stimulation through electrodes located predominantly in a region extending from the preoptic area through the lateral hypothalamus into the ventral midbrain. Escape and digging were elicited from a parallel but more medial region that overlapped the lateral zone only in the preoptic-anterior hypothalamic area. Several differentiable vocalizations were produced from sites distributed through most, although not all, areas explored. Sites yielding painlike responses were located principally in the vicinity of the presumed pain pathway traced after anterolateral cordotomy in other species. Reward was obtained from widespread sites that were generally congruent with catecholaminergic systems as described in the rat. Although there was considerable overlap of the effective zones for many responses, their underlying mechanisms were differentiated anatomically by localized differences in their distribution or functionally by the elicitation of pure responses from some electrodes. Response mechanisms localized in the brain stem of the guinea pig generally resembled those in the rat, although there were differences in details, especially in the posterior midbrain and pons.     

On the synchrony of stopping motor responses and delaying heartbeats.

Recent evidence suggests that inhibition of a motor response may occur as late as the final stages of response execution. Response production involves central commands for autonomic support as well as motoric action. Autonomically controlled responses were used in conjunction with electromyographic and performance indices to examine the timing and flexibility of inhibition. Twenty young male Ss performed a choice reaction time task with stimuli timed according to when they occurred in relation to the R wave of the electrocardiogram. Stop signals, presented on 30% of the trials, induced inhibition. The performance and physiological results generally supported the horse-race model of inhibition. Inhibition was observed as late as during response execution. A short-latency, phasic lengthening of interbeat interval was suggested to reflect the midbrain coordination of the countermanding of response execution.     

Activation of midbrain structures by associative novelty and the formation of explicit memory in humans

Recent evidence suggests a close functional relationship between memory formation in the hippocampus and dopaminergic neuromodulation originating in the ventral tegmental area and medial substantia nigra of the midbrain. Here we report midbrain activation in two functional MRI studies of visual memory in healthy young adults. In the first study, participants distinguished between familiar and novel configurations of pairs of items which had been studied together by either learning the location or the identity of the items. In the second study, participants studied words by either rating the words' pleasantness or counting syllables. The ventral tegmental area and medial substantia nigra showed increased activation by associative novelty (first study) and subsequent free recall performance (second study). In both studies, this activation accompanied hippocampal activation, but was unaffected by the study task. Thus midbrain regions seem to participate selectively in hippocampus-dependent processes of associative novelty and explicit memory formation, but appear to be unaffected by other task-relevant aspects.